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NEUROBIOLOGY OF LEARNING AND MEMORY

ARTICLE NO.

68, 285–316 (1997)

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Memory Formation: The Sequence of Biochemical
Events in the Hippocampus and Its Connection
to Activity in Other Brain Structures
Ivan Izquierdo* and Jorge H. Medina†,1
*Departamento de BioquıB mica, Instituto de Cieˆncias Ba´sicas da Sau´de, Universidade Federal
do Rio Grande do Sul, Ramiro Barcellos 2600, 90035-003 Porto Alegre, RS, Brazil; and
†Laboratorio de Neurorreceptores, Instituto de BiologıB a Celular, Facultad de Medicina,
Universidad de Buenos Aires, Paraguay 2155, 3er Piso, Buenos Aires, Argentina

Recent data have demonstrated a biochemical sequence of events in the rat hippocampus that is necessary for memory formation of inhibitory avoidance behavior. The
sequence initially involves the activation of three different types of glutamate receptors
followed by changes in second messengers and biochemical cascades led by enhanced
activity of protein kinases A, C, and G and calcium–calmodulin protein kinase II,
followed by changes in glutamate receptor subunits and binding properties and increased expression of constitutive and inducible transcription factors. The biochemical
events are regulated early after training by hormonal and neurohumoral mechanisms
related to alertness, anxiety, and stress, and 3–6 h after training by pathways related
to mood and affect. The early modulation is mediated locally by GABAergic, cholinergic,
and noradrenergic synapses and by putative retrograde synaptic messengers, and extrinsically by the amygdala and possibly the medial septum, which handle emotional
components of memories and are direct or indirect sites of action for several hormones
and neurotransmitters. The late modulation relies on dopamine D1 , b-noradrenergic,
and 5HT1A receptors in the hippocampus and dopaminergic, noradrenergic, and serotoninergic pathways. Evidence indicates that hippocampal activity mediated by glutamate AMPA receptors must persist during at least 3 h after training in order for
memories to be consolidated. Probably, this activity is transmitted to other areas,
including the source of the dopaminergic, noradrenergic, and serotoninergic pathways,
and the entorhinal and posterior parietal cortex. The entorhinal and posterior parietal
cortex participate in memory consolidation minutes after the hippocampal chain of
events starts, in both cases through glutamate NMDA receptor-mediated processes,
and their intervention is necessary in order to complete memory consolidation. The
hippocampus, amygdala, entorhinal cortex, and parietal cortex are involved in retrieval
in the first few days after training; at 30 days from training only the entorhinal and
parietal cortex are involved, and at 60 days only the parietal cortex is necessary for
retrieval. Based on observations on other forms of hippocampal plasticity and on memory formation in the chick brain, it is suggested that the hippocampal chain of events
that underlies memory formation is linked to long-term storage elsewhere through
activity-dependent changes in cell connectivity. q 1997 Academic Press

1
This work was supported by PRONEX, Brazil, and University of Buenos Aires, Argentina.
Address correspondence and reprint requests to Dr. Ivan Izquierdo, Departamento de BioquıB mica, Instituto de Cieˆncias Ba´sicas da Sau´de, Universidade Federal do Rio Grande do Sul, Av.
Ramiro Barcellos 2600, 90035-003 Porto Alegre, RS, Brazil. Fax: 55 51 316 5535.

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IZQUIERDO AND MEDINA

Step-down inhibitory (passive) avoidance learning in the rat triggers biochemical events in the hippocampus that are necessary for the retention of
this task. The events are similar in many ways to those described for different
types of long-term potentiation (LTP) and other forms of neural plasticity
(Baudry, Bi, & Tocco, 1996; Bliss & Collingridge, 1993; Collingridge & Bliss,
1993; Izquierdo & Medina, 1995, 1997; Maren & Baudry, 1995; Martin &
Kandel, 1996; Reymann, 1993). They are triggered by glutamate receptor activation and involve at least four different biochemical cascades led by different
protein kinases: Protein kinase G (PKG) (Bernabeu, Schro¨der, Quevedo, Cammarota, Izquierdo, & Medina, 1997c), protein kinase C (PKC) (Bernabeu, Izquierdo, Cammarota, Jerusalinsky, & Medina, 1995a; Bernabeu, Cammarota,
Izquierdo, & Medina, 1997b), calcium–calmodulin-dependent protein kinase
II (CaMKII) (Bernabeu et al., 1997b; Wolfman, Fin, Dias, Bianchin, Da Silva,
Schmitz, Medina, & Izquierdo, 1994), and protein kinase A (PKA) (Bernabeu,
Bevilaqua, Ardenghi, Bromberg, Schmitz, Bianchin, Izquierdo, & Medina,
1997a; Bevilaqua, Ardenghi, Schro¨der, Bromberg, Schmitz, Schaeffer, Quevedo, Bianchin, Walz, Medina, & Izquierdo, 1997) (Fig. 1).
Several steps of these cascades have been implicated in other forms of learning that also involve the hippocampus (Abel, Nguyen, Barad, Deuel, Kandel &
Bourchuladze, 1997; Bliss & Collingridge, 1993; Guzowski & McGaugh, 1997;
Izquierdo, Da Cunha, Rosat, Jerusalinsky, Ferreira, & Medina, 1992; Izquierdo & Medina, 1995; Mayford, Bach, Huang, Wang, Hawkins, & Kandel,
1996; Nogue`s, Micheau, & Jaffard, 1994; Tan & Liang, 1996; Tocco, Devgan,
Hauge, Weiss, Baudry, & Thompson, 1991; Wilson & Tonegawa, 1997), in
another form of inhibitory avoidance in the chick brain (Anokhin, Mileusnic,
Shamakina, & Rose, 1991; Rose, 1995a,b; Zhao, Polya, Wang, Gibbs, Sedman, & Ng, 1995), and in other forms of neural plasticity (Abel et al., 1997;
Bartsch, Ghirardi, Skehel, Karl, Herder, Chen, Bailey, & Kandel, 1995; Beninger & Nakonechny, 1996; Bliss & Collingridge, 1993; Carew, 1996; Huang,
Colley, & Routtenberg, 1992; Reymann, 1993; Yin & Tully, 1996). Most of the
evidence for the role of these processes in memory formation comes from studies on the effect on memory of infusions of specific receptor agonists and antagonists or enzyme inhibitors at various times after inhibitory avoidance training
into the hippocampus and elsewhere and from detailed biochemical or histochemical analysis of these receptors and enzymes in the same structures, also
at various times after training (Izquierdo & Medina, 1995, 1997). Several of
the findings have been corroborated in other tasks using the same techniques
(Izquierdo & Medina, 1995, 1997), and, more recently, by second-generation
gene knockout studies in mouse hippocampus (Mayford et al., 1996; Wilson &
Tonegawa, 1997).
Step-down inhibitory avoidance involves learning not to step down from a
platform in order to avoid a mild footshock. It is usually acquired in one
single trial, which makes it ideal for studying processes initiated by training,
uncontaminated by prior or further trials, rehearsals, or retrievals (Gold, 1986;
Izquierdo, 1989). Step-down avoidance involves the specific repression of the
natural tendency of rats to explore beyond the platform, without affecting the
performance of exploratory behavior while on the platform, repeated approximations to its border, or abortive step-down responses; for these reasons we
prefer the term ‘‘inhibitory’’ to ‘‘passive’’ (Netto & Izquierdo, 1985). There are
many variants of inhibitory avoidance: In rodents, not to step through a door
into a compartment where they receive footshocks; in flies, not to enter a foul-

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HIPPOCAMPAL BIOCHEMISTRY AND MEMORY

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odored area; in chicks, not to peck a bitter bead; in humans, to refrain from
putting the fingers in the electrical outlet or from crossing a street without
looking. Obviously, this task represents one of the major determinants of survival behavior in all species (Gold, 1986), and the brevity of its acquisition
should not mislead into thinking that it is inborn or implicit. Indeed, there is
a seldom-measured implicit component of this task (bradycardia) that, unlike
its explicit component (increased avoidance latency), is insensitive to electroconvulsive shock (Hine & Paolino, 1970). The declarative component of this
task, like that of many others (Calderazzo Filho, Cavalheiro, & Izquierdo, 1977;
Eichenbaum, 1996; Gabrielli, Brewer, Desmond, & Glover, 1997; Izquierdo et
al., 1992; Izquierdo & Medina, 1991, 1995; Matthies, 1982, 1989; Squire, 1992;
Tocco et al., 1991; Vnek & Rothblat, 1996), crucially involves the hippocampus
(Izquierdo et al., 1992; Izquierdo & Medina, 1991, 1995, 1997; Lorenzini, Baldi,
Bucherelli, Sacchetti, & Tassoni, 1996; O’Connell, O’Malley, & Regan, 1997).
Carew (1996) recently observed that ‘‘typically, the encoding of a lasting
memory entails considerable practice and rehearsal, but . . .rare events in
our life . . .are so powerful as to be instantly recorded and remembered for
a lifetime.’’ An afferent volley such as that used in order to induce LTP in
rats, or the association of a given experience with a footshock or a strong
taste, such as that used for inhibitory avoidance conditioning in rats and
chicks, respectively, or a strong odor such as that used for training in the
fly, or a jet of 5HT in the mollusk ganglion certainly constitute ‘‘rare’’ and
‘‘powerful’’ events and induce pronounced biochemical changes. It is presumed that similar changes occur to a lesser degree, or in a smaller number
of synapses, in less dramatic memories (Carew, 1996; Izquierdo & Medina,
1997; Yin & Tully, 1996). The presumption is based on a large body of evidence showing that the effects of many of the drugs that alter the memory
of inhibitory avoidance and many of the hippocampal biochemical changes
are also seen following exploratory habituation and other tasks (Izquierdo et
al., 1992; Izquierdo & Medina, 1995; Matthies, 1982, 1989; Rose, 1995a;
Tan & Liang, 1996; Wolfman, Da Cunha, Jerusalinsky, Levi de Stein, Viola,
Izquierdo, & Medina, 1991).
THE HIPPOCAMPAL BIOCHEMICAL CASCADES
OF INHIBITORY AVOIDANCE LEARNING
The Initial Role of Glutamate Receptors
The biochemical events underlying memory formation of the inhibitory
avoidance task in the hippocampus involve, first, an activation of NMDA,
AMPA, and metabotropic glutamate receptors, and a short-lasting increase
of NMDA1 levels and a longer lasting increase of GluR1 levels (see below)
(Izquierdo & Medina, 1995, 1997; Medina & Izquierdo, 1995). Immediate but
not delayed (30–180 min) intrahippocampal infusion of the NMDA antagonist
aminophosphonopentanoic acid (AP5) (Izquierdo et al., 1992; Jerusalinsky,
Ferreira, Da Silva, Bianchin, Ruschel, Medina, & Izquierdo, 1992) or of the
glutamate metabotropic receptor antagonist methyl-carboxyphenyl glycine (Bianchin, Da Silva, Schmitz, Medina, & Izquierdo, 1994) is amnestic. Immediate
posttraining intrahippocampal infusion of glutamate or of the metabotropic
agonist aminocyclopentane dicarboxylate causes retrograde memory facilitation (Bianchin et al., 1994; Izquierdo et al., 1992). Intrahippocampal adminis-

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Princ. 1995. sharply increases immediately after training and returns to normal a few minutes later. 1997. The role of hippocampal AMPA receptors in memory formation was discussed by Jerusalinsky et al. & Medina. Juknat. Son. 1995). & Mishina. (1992) and by Cammarota. the enzyme that produces CO (Bernabeu. particularly those that involve distant visual cues. muscimol is amnestic and picrotoxin facilitates memory) and to modulation by cholinergic muscarinic AID NLM 3799 / 6v12$$$$62 10-21-97 23:52:05 nlmoal AP: NLM . Alzawa. Izquierdo & Medina. & Medina. 1997. and of heme oxygenase. carbon monoxide (CO). which indicates that hippocampal excitation mediated by these receptors is necessary for memory formation during that period.. Huang. has been studied by several authors (see references in Bliss & Collingridge. Kushiya. memory formation is very sensitive to inhibition by GABAA receptors (when given into CA1. 1997). Izquierdo. 1995. Inoue. Takayama.. 1995b) or of a soluble form of the platelet activating factor (mcPAF) (Izquierdo. 1993). Yagi. and the platelet activating factor (PAF) in the early phase of memory formation of the step-down task in the hippocampus (Medina & Izquierdo.. Izquierdo. Manabe. Anderson. Bernabeu. of a NO synthase inhibitor (Bernabeu et al. Martin. 1995). The role of metabotropic glutamate receptors in memory formation in this and other tasks has been recently discussed by Reymann (1993) and Riedel (1996). 1993. Fin.. Recently. 1992). Fin. The role of hippocampal NMDA receptors in memory formation has been discussed by numerous authors (see Izquierdo & Medina. Fishman. & Bazan. 1995) causes memory facilitation. Kutsuwada. for references). 1995. 1995c). 1993. nitric oxide (NO). and Baudry (1986). the first authors to suggest this were Morris. 1997). The role is much clearer than the one proposed for these substances in LTP induction (see Bliss & Collingridge. The activity of NO synthase (Bernabeu et al. or of a heme oxygenase inhibitor (Bernabeu et al. Batlle. Medina. Lynch. Early Involvement of Putative Retrograde Messengers Evidence suggests a participation of the putative retrograde messengers that regulate glutamate release. Medina & Izquierdo. Jerusalinsky. Levi de Stein. 1995c) causes retrograde amnesia for this task. Sugiyama. selective knockout of the gene that encodes for the NMDA1 receptor subunit in mouse CA1 was shown to disrupt both place cell ensemble activity and memory of spatial memory (Wilson & Tonegawa. Hawkins. The role of hippocampal NMDA receptors in several forms of learning. Da Silva. Ferreira. Reymann. Immediate but not delayed (30 min) infusion into CA1 of a PAF antagonist (Izquierdo et al. Levi de Stein. Ito. Fin. A similar previous finding had been obtained using first-generation (whole body) deletion of the NMDAR1 gene (Sakimura. and Medina (1996). studying the effect of chronic intracerebroventricular AP5 release by a micropump on spatial learning in a water maze.288 IZQUIERDO AND MEDINA tration of the AMPA receptor antagonist cianonitroquinoxaline-dione (CNQX) causes amnesia for the inhibitory avoidance task when given up to 3 h after training (Jerusalinsky et al. The immediate but not the delayed (30 min) intrahippocampal infusion of the NO releaser S-nitrosoN-aminopenicillin (Bernabeu. Izquierdo. Actually.. & Kandel. 1995b). Quillfeldt. Early Modulation by GABAA and Other Receptors In the first few minutes after training. Kiebler. 1995). 1995b).

1997). 1997b). but as much as 168 h in CA3 and in the dentate gyrus (Cammarota et al. and a slow rise of the levels of GluR1 that starts about 30 min after training and peaks at approximately 3 h (Bernabeu et al. Izquierdo et al. but no doubt they reflect increased excitability of hippocampal neurons. 1992). 1995) that lasts about 3 h in CA1 and CA2. The significance of such changes is not known. alertness. Tan. Ample evidence suggests that the amygdala (Bevilaqua et al. 1996). Bernabeu. 1992. and GluR1 is a specific subunit of AMPA receptors. the activity of these two enzymes in hippocampus increases right after training. CNQX.. 1992. Izquierdo & Medina. 1993. 1990.. Bueno e Silva. Wolfman et al. 1982. The regulation of AMPA (and NMDA) receptors by PKA.HIPPOCAMPAL BIOCHEMISTRY AND MEMORY 289 and b-noradrenergic receptors (when given into CA1.. Gray. 1995..and CaMKII-mediated phosphorylation has been well established in various synapses of the rat brain (McGlade-McCulloh. Yamamoto. Brickey. 1991) are involved in the processing of anxiety. Jerusalinsky. but also its Bmax for AMPA and the actual amount of GluR1 measurable by immunoblot (Bernabeu et al. Medina. Maren. Incubation of synaptic membranes under conditions of optimum phosphorylation by CaMKII and/or PKA increases not only phosphorylation of the subunit. Bernhardt & Huganir. muscimol. a supposition that later evidence proved erroneous (see below and Izquierdo & Medina. 1992) and to an extent the medial septum (Gray. O’Brien. Increased AMPA binding has been reported in the hippocampus after LTP by Tocco. (1991) following eye-blink conditioning. picrotoxin. norepinephrine and oxotremorine facilitate memory. Izquierdo. 1996. Walz et al. The GluR1 increase occurs concomitantly with a slow rise of Bmax of AMPA to AMPA receptors in synaptic membranes extracted from all hippocampal subregions (Cammarota. The increase of GluR1 levels measured by immunoblot in CA1 synaptosomal membranes seen after training may correlate with phosphorylation of the subunit by CaMKII and PKA (see below). & Soderling. 1991. 1991. 1997. and PAF) have been also observed studying immediate posttraining infusions into the amygdala and medial septum (see Izquierdo et al. Mammen. norepinephrine. & Medina. 1997. Changes in Glutamate Receptor Properties In synaptic membranes extracted from CA1 there is a short-lived increase of NMDA1 levels measured by immunoblot at 30 min from training. Pasqualotto & Shaw. Jerusalinsky et al. Walz et al. Levi de Stein. 1997c). As will be commented further on. Baudry.. Da Silva. 1982.. and Thompson (1992) and by Tocco et al. Involvement of Extrahippocampal Structures Several of the findings mentioned above (effect of AP5. Cahill & McGaugh. Fedorov.... Wolfman. and timolol alters sensitivity to GABAergic modulation. Shors.. & Izquierdo. 1997.. Walz. 1992). and Reymann (1993) have reported increased electrophysiological sensitivity of hippocampal AMPA receptors to AMPA in the first 90 min after LTP. NMDA1 is a specific subunit of NMDA receptors. 1996). which may underlie plastic changes in their output to projection sites. Izquierdo & Medina. Roche. timolol. 1992. scopolamine is amnestic. oxotremorine. AID NLM 3799 / 6v12$$$$62 10-21-97 23:52:05 nlmoal AP: NLM . or aversiveness. Sergueeva. 1996. alongside those in the hippocampus (Izquierdo et al. Izquierdo & Medina. 1992). This led to the supposition that LTP-like phenomena in these other structures might be involved in memory consolidation. scopolamine.

Izquierdo.5 mg/side) or 8-Br-cGMP (1. Faillace. whereas that of the guanylyl cyclase inhibitor LY83583 is amnestic (Bernabeu et al. and behavioral effects of LY83583 (2. the enzyme that synthesizes cyclic guanosyl monophospate (cGMP) (Zhuo. The biochemical data in the ordinates are expressed as means { SEM % of shocked controls (animals placed on the grid of the apparatus and exposed just to the footshock without avoidance training). rapid. in min.01 and **p õ . (1996.05. Schmitz. & Hawkins. Kandel.. The behavioral data are means { SEM test minus training step-down latencies expressed as a % of those from saline. and test session performance data of rats that received bilateral drug infusions into CA1 at various times after training. but very briefly. Endogenous cGMP levels in rat CA1 increase markedly. and cGMP may induce long-lasting synaptic potentiation in hippocampal CA1 (Zhuo.290 IZQUIERDO AND MEDINA FIG. This figure shows data relevant to the cGMP/PKG cascade: cGMP levels measured by radioimmunoassay in CA1 (tilted solid squares).3-mA footshock. Both cGMP levels and PKG activity rise immediately after training and return to normal 30 min later.. when given 0 but not 30 min posttraining. soon after inhibitory avoidance training and return to normal levels between 30 and 60 min later (Bernabeu et al. PKG activity in CA1 measured using peptide G-5611 as substrate (solid squares). The immediate but not the delayed (30–180 min) infusion into CA1 of 8-BrGMP causes memory facilitation of step-down avoidance (Bernabeu. Thus. AID NLM 3799 / 6v12$$$$62 10-21-97 23:52:05 nlmoal AP: NLM . This and all the following figures show biochemical data of hippocampal CA1 regions of rats sacrificed at various times after step-down inhibitory avoidance training with a 0. These findings point to an early.or vehicle-treated controls. and necessary intervention of cGMP and PKG in memory consolidation. The cGMP/PKG Cascade NO and CO activate soluble guanylyl cyclase. & Medina. 1997c). 1). Time of sacrifice or infusion is shown in the abscissae. 1994a). Kandel.. 1994a). 1996). and 8-Br-cGMP causes retrograde memory facilitation. LY83583 causes retrograde amnesia.. CO. 1997c) (Fig. & Hawkins. Asterisks indicate significant differences from controls in Newman– Keuls tests: *p õ . Data are from Bernabeu et al. Guanylyl cyclase activity increases immediately after training and returns to normal 30 min later (Bernabeu et al. NO. 1994b) and the cGMP protein kinase (PKG) appears to be crucial for CA1 LTP (Zhuo et al. 1. Schultz. Hu.25 mg/side) infused into CA1. 1997c). 1996).

KN62. which was confirmed by later studies using specific inhibitors (Ito. (1997). 1994a. as well as firstgeneration (whole body. who infused the specific inhibitor of this enzyme. & Matthies. and infusions 2 –4 h after training into either structure were ineffective. & Mu¨ller. de Freitas. presynaptic guanylyl cyclase is supposedly a target of NO and CO action. respectively). and Medina & Izquierdo. This suggested that CaMKII plays an essential role in the hippocampus (and amygdala) in the first few minutes after training. These possibilities await further study. Stoppini. 1997). (1996).. 1991) and enzyme assays (Fukunaga. Pasqualotto and Shaw (1996). Subsequently. Roche et al. respectively. Pessoa-Pureur. CaMKII has been suggested early on to play a key role in the early postinduction phase of LTP (Reymann et al. 1996). Lisboa. and PKG activation might help in the mobilization of glutamatergic synaptic vesicles toward the synaptic cleft (see Zhuo et al. Brodemann. 1996). We were AID NLM 3799 / 6v12$$$$62 10-21-97 23:52:05 nlmoal AP: NLM . or in other areas of the brain (Bliss & Collingridge. Miyamoto. There is so far no indication of what PKG substrates may be involved in memory processing in the first few minutes that follow acquisition. 1994a). however. & Stryker. For reviews of these aspects. Intrahippocampal infusion of the drug 30 min after training had only a partial amnestic effect. A very strong amnestic effect was obtained when the inhibitor was infused immediately posttraining into hippocampus or amygdala. 1988). The time course of the intervention of CaMKII in hippocampal CA1 or CA3 LTP more or less overlaps with that of PKC. Silva. & Planas. the functions subserved by CaMKII and PKA are also different. Blanco. CREB (Ferrer. as it does in LTP in the first few minutes after induction (Ito et al.. into CA1 or into the amygdala at different times after step-down inhibitory avoidance training. 1995.. 1991. Carmona. (1996). 1996) and secondgeneration transgenic studies (localized to CA3. Mayford et al. 1988). Hidaka. 1993). & Izquierdo. and Schro¨der et al. for references). Reymann. de Mattos-Dutra. 1993).HIPPOCAMPAL BIOCHEMISTRY AND MEMORY 291 perhaps as in LTP (Zhuo et al. In all these cases. & Sugiyama. and neurofilaments and other structural proteins (Schro¨der. see Ferrer et al. The first evidence for an involvement of CaMKII in memory processing in hippocampus and amygdala was provided by Wolfman et al. since the sites of each of these proteins that are phosphorylated by the two enzymes are different. In LTP. the evidence indicates that the cGMP/ PKG cascade in CA1 is crucial early on for the long-term plasticity of inhibitory avoidance (Kim. it acts concomitantly with PKA. Not surprisingly. (1994). Cioffi. except that the peak of CaMKII activity occurs earlier and the increase of activity lasts less than that of PKC (see Reymann. including the ionotropic glutamate receptors (see above). 1996. Ballabriga. Olive´.. Tan and Liang (1996) reported similar findings on the amnestic effect of CaMKII inhibitors in a spatial learning task and showed a posttraining increase of CaMKII activity following training in that task.. 1993). Gordon. Zilles. Rivera. The CaMKII Cascade CaMKII activity is regulated by the increase of intracellular Ca2/ that follows activation of NMDA receptors or the entry of Ca2/ through voltagedependent channels that trigger LTP in CA1 and in CA3. Ka¨se. CaMKII mediates the phosphorylation of a variety of proteins of importance in synaptic plasticity..

and only partially when given 30 min later. The data show a necessary participation of CaMKII in memory consolidation in the first few min after training and of AMPA receptors from 0 to 3 h after training. CA1 levels of the AMPA receptor subunit. Changes in the phosphorylation levels of neurofilament proteins of rat hippocampus. (1994) using Kn62.e. 1997b). [3H]AMPA binding to AMPA receptors in CA1 (bars). solid triangles) and of the CaMKII inhibitor KN62 (3. GluR1 levels. (1994). CaMKII activity increased in the first half hour after training.. we found that Ca2/-independent b-CaMKII activity increased slightly immediately after training and returned to normal in 30 min. (1997b). Autophosphorylation of the enzyme (i. In addition. 1997b). 1997). when given up to 180 min posttraining. Ca2/-dependent to the inactive. 1997b). Ca2/-dependent a-CaMKII activity increased markedly right after training. Ca2/-independent form) was maximal immediately after training (Bernabeu et al. (1992). the former.6 mg/side. Both CNQX and KN62 caused retrograde amnesia. 2) (see Bernabeu et al.. Ca2/-dependent (shaded squares) and Ca2/-independent (crosses) CaMKII activity in CA1 measured using Syntide-2 as substrate. 1997b). the Ca2/-dependent activity increased more and remained high for a longer time than the Ca2/-independent activity. have been observed 60 min after either step-down inhibitory avoidance training or the habituation of exploration of the training apparatus (Schro¨der et al.. and AMPA binding increased gradually from 30 min after training on. open triangles) infused into CA1. Data from Jerusalinsky et al. the latter only when given up to 180 min posttraining. AID NLM 3799 / 6v12$$$$63 10-21-97 23:52:05 nlmoal AP: NLM . and returned to normal in 120 min (Bernabeu et al.25 mg/side. GluR1 measured by immunoblot (open squares) and GluR1 phosphorylation (tilted crosses).. 2. Cammarota et al. These data are the mirror image of those that were obtained by Wolfman et al. GluR1 phosphorylation.. conversion from the active. able to confirm and complement these findings using the step-down inhibitory avoidance task (Fig.292 IZQUIERDO AND MEDINA FIG. decreased slightly but still remained high at 30 min. (1996. 1997).. Wolfman et al. The CaMKII cascade. and Bernabeu et al. and behavioral effects of CNQX (1. which is mediated by CaMKII and by PKA. Various data in the literature suggest that the latter depends on the former (see Bernabeu et al. the latter only when given immediately after training.

1990) and eye-blink conditioning (Scharenberg. it stimulates adenylyl cyclase and therefore cAMP synthesis (Yoshimura & Cooper. including glutamate and acetylcholine (Bliss & Collingridge. PKC is redistributed from cytoplasm to membrane in rat hippocampal CA3 after discrimination learning (Olds.. the suggestion arose that PKC may be involved in memory formation.. Actually. As is known. Olds. Schro¨der. Ardenghi. 1995. Reymann. Potter. 1985). Golski. and Rose (1990). Silva. like Ca2/. Horn. Nogue`s et al.. 1995. 1994). we have observed that the retrograde amnesia caused by systemic b-endorphin administration or by electroconvulsive shock can be reversed by pretest administrations of adrenocorticotropin or vasopressin (see Bohus. and Bennett (1994) reported on the amnestic effect of PKC and other protein kinase inhibitors administered into the chick brain in this task. including some that are clearly modulatory. whereas the amnesia induced by the CaMKII inhibitor KN62 given intrahippocampally 0 h after training or that induced by the PKA inhibitor KT5720 given intrahippocampally 3 h after training cannot be reversed by the hormones. first the postsynaptic g isoform of PKC is activated and then the presynaptic b isoform. 1992. Rosenzweig. Izquierdo. This further illustrates that CaMKII and PKA (see next section) participate in the core mechanism. RodrıB guez. Craig & Alkon. which phosphorylates the presynaptic protein GAP-43 (Routtenberg. plays a crucial role in the activation of PKA and the triggering of another cascade of great importance in the long-term persistence of memory and other plastic events. Colley & Routtenberg. abundant proof that memory formation in the chick depends on membrane-bound protein kinase C was provided several years earlier by Bourchuladze. & Alkon. Quevedo. 1989. which. I. Izquierdo & Medina. and is essential for the continuation of LTP beyond the induction phase (Ben-Ari. In view of the many similarities between the hippocampal biochemistry of memory and that of LTP (Bliss & Collingridge. Recently (L. Chen. 1993). 1997).HIPPOCAMPAL BIOCHEMISTRY AND MEMORY 293 An elegant general confirmation of the importance of a-CaMKII in learning processes has been obtained using regulated expression of the CaMKII transgene localized to the CA3 region of the hippocampus (Mayford et al. like systemically administered b-endorphin (see Izquierdo. 1997. Benistan. McGaugh. 1991). Kornisiuk. A. Anikstejn. Stevens & Tonegawa. of memory in the hippocampus. as will be seen below. and not in a modulatory mechanism. Mishkin. McCabe. & Bergestovski. McPhie. Transgenic mice with a knockout of the gene that encodes for gPKC in the whole organism (i. Oxonian. 1997) showed impaired hippocampal LTP (Abeliovich. 1993.. Sheu. Reymann et al. and Routtenberg (1993) reported increased PKC substrate phosphorylation in specific regions of the chick brain after inhibitory avoidance.e. 1996). 1989). (1994) detected increased PKC activity in mouse hippocampus following a spatial task. & Medina. & Izquierdo. see Wilson & Tonegawa. first-generation knockouts. 1992). Netto. Olton. Huang et al. The PKC Cascade PKC is activated by various transmitters. Izquierdo. 1993). PKC inhibitors given early after induction block LTP (Huang et al. Schereurs. Bevilaqua. 1992. Jerusalinsky. retrograde amnesia for the inhibitory avoidance task can be induced by a variety of agents. In LTP. 1997b). Lovinger & Stewart. Goda. 1988). 1993a) and spatial and contextual learning (Abeli- AID NLM 3799 / 6v12$$$$63 10-21-97 23:52:05 nlmoal AP: NLM . Maren & Baudry. One important feature of PKC is that. 1993. 1993.. Serrano.

CGP41231 is fully amnestic when given 0 or 30 min posttraining into CA1. Da Silva.294 IZQUIERDO AND MEDINA FIG. Izquierdo. depend on the hippocampus (Eichenbaum. PKC levels rise immediately after training. the LTP and learning changes seen in g-PKC mutants. correlate well with those predicted from pharmacological or biochemical experiments (see below). The amnesia was complete when the drugs were given into hippocampus or amygdala up to 60 min after training. GAP-43 phosphorylation reaches a peak at 30 min. and partial when the infusion was delayed for 120 min. phosphorylation of the PKC substrate GAP-43 in CA1 (triangles). within the first 120 min after step-down inhibitory avoidance training. & Bunsey.5 h later.0 h. we measured posttraining PKC activity by two different methods: One less specific (phorbol dibutyrate binding. Quillfeldt.. Schoenbaum. starting immediately after step-down avoidance training. Bernabeu. staurosporin and CGP41231. 3. and behavioral effect of the PKC inhibitor CGP41231 (2. 1996. 3). Paratcha. Subsequently. intra-amygdala. or intraentorhinal (Jerusalinsky et al. Levi de Stein. 1995a). and returning to normal values over the next 2. and return to normal at 120 min. Kim. (1997) and Jerusalinsky et al. reaching a peak 0. Cammarota. A similar AID NLM 3799 / 6v12$$$$63 10-21-97 23:52:05 nlmoal AP: NLM . Paylor. Chen. Eichenbaum. Data from Cammarota et al. 1993b). blocked memory expression of this task measured 24 h later (Fig. (1994b). Walz. & Medina. Both experiments revealed a very large increase of membrane-bound PKC activity in hippocampus relative to shocked and naive controls. 3). A similar effect has been reported for another PKC inhibitor. however. reach a peak at 30 min. alterations all over the body) can be found in Maren and Baudry (1995).. The data point to a necessary role of PKC activity in CA1 in memory consolidation in the first 30 min after training. Criticisms of first-generation transgenic experiments (developmental variables. Medina & Izquierdo. Fig. ovich. Young. and Wilson and Tonegawa (1997). two declarative tasks that. 1997.. Routtenberg (1995). 1994b). Wehner. 1994b). and another one very specific (using a synthetic peptide substrate.5 mg/side) infused into CA1. Bernabeu et al. We observed that the intrahippocampal (Jerusalinsky. and partially amnestic when given at 120 min. 1996). PKC activity measured in CA1 by in vitro phosphorylation using histone IIIS as substrate (squares). & Tonegawa. adaptive changes. 1992) infusion of two different PKC inhibitors. The PKC cascade. like most others. staurosporin (Jerusalinsky et al.

b). odor conditioning in the fruit fly Drosophila (Tully. 1995). 1996). 1996. & Kandel. 1997a). The coincidence of the time course of the change of hippocampal PKC activity with that of the amnestic effects of the PKC inhibitors (see above) points to a clear and crucial involvement of this enzyme in the posttraining memory processing of this task. 1994. GAP-43. 1993.. 1997a. the increase is not accompanied by changes in the activity of cAMP-specific phosphodiesterase. 1996. Schuster. Yin & Tully. Bevilaqua et al. 1994. 1997b). Carew. PKA activity increases after training. Huang & Kandel. Frenguelli. when phosphorylated (CREB-P) (Davis et al. As found by Routtenberg et al. long-term neuromuscular junction plasticity in Drosophila (Davis.. parietal. 1995. at least in part. Like LTP (Frey.. Li. 1996. in two peaks: The first. the biochemical events triggered by inhibitory avoidance learning in rat hippocampus.b. and entorhinal cortex. Reymann. 1996). 1996). GAP-43 has been proposed to be involved in the generation of activity-dependent synaptic morphological changes (Benowitz & Routtenberg. (1985) following LTP. 1997). Martin & Kandel. 5HT-induced facilitation in the mollusk Aplysia (Bartsch et al. 3 to 6 h after training (Fig. Blendy..c. reaching a peak 180–360 min after training. 1996. immediately after training.. which coincided with the PKC activity peak and was blocked. & Silva. Bevilaqua et al. The function of hippocampal PKC in memory is as unclear as it is in LTP (see Colley & Routtenberg. 4). The cAMP/PKA/CREB-P Cascade Like LTP in rat hippocampus (Grant & Silva. a function which may be important for long-term memory (see below). in the amygdala and in the frontal. and the second. 1997). 1996. and to a lesser degree in cerebellum (Bernabeu et al. 1995a). Ferrer et al. 1996. 1996). involve the late intervention of a cyclic adenylyl monophosphate (cAMP)/PKA/CREB (cAMP response element-binding protein) signaling pathway (Bernabeu et al.. suggesting that it is due to enhanced adenylyl cyclase activity (Bernabeu et al. Tully. like the latter. CREB is a family of transcription factors that regulate the synthesis of a number of proteins. and. 1996. The second peak correlates with the maximum rise of cAMP levels after training and may be triggered by it (Bernabeu et al. by diverse PKC inhibitors (Cammarota et al. Yin & Tully. spatial learning in the mouse (Bourchuladze.HIPPOCAMPAL BIOCHEMISTRY AND MEMORY 295 pattern of changes was observed. Bito. AID NLM 3799 / 6v12$$$$63 10-21-97 23:52:05 nlmoal AP: NLM . 1994)... & Tsien. 1997). Cioffi.. 1995a.. with less intensity. 1996. Huang.. memory of step-down inhibitory avoidance is enhanced by the intrahippocampal administration of the 8-Br analog of cAMP or by stimulators of adenylyl cyclase 3 or 6 h after training (Bernabeu et al. including inducible transcription factors. No changes were observed in other brain structures. & Goodman. 1994). Schutz.. Zhao et al.. higher. Huang.. It is not known what triggers the earlier peak of PKA activity (Bernabeu et al. Deisseroth. 1993). 1993). we detected 30 min after avoidance training a brief peak of enhanced PKC-mediated phosphorylation of the presynaptic protein. inhibitory avoidance in the chick (Rose. 1995). 1997a–c. 1996. 1997). PKA-mediated CREB-P activation modulates gene activation and protein synthesis critical for persistence of all the forms of plasticity mentioned above beyond 3 or 4 h (Bourchuladze et al. 1997a. Hippocampal cAMP levels slowly increase beginning 60 min after step-down inhibitory avoidance training. & Kandel.

The PKA inhibitor was amnestic when given 0. The PKG cascade lasts less than 30 min. 4).296 IZQUIERDO AND MEDINA FIG. Izquierdo & Medina. 1995. Zhuo et al. remained high at 360 min. thus. 1993. and CREBP (gray squares) and c-fos (tilted crosses) measured by immunohistochemistry. There is. 4). The cAMP/PKA/CREB-P cascade. Huang et al. Data from Bernabeu et al. The data fit with those that have been described for hippocampal LTP (see Bliss & Collingridge. PKA activity measured using Kemptide as a substrate (solid squares). 1996. CREB-P levels in the CA1 region also increase after step-down avoidance training. but not 60 or 540 min after training. Reymann. larger. and the PKA increase occurs in two peaks.5 mg/side. both PKA values and CREB-P levels returned to normal at 540 min from training. 1994a. open triangles) and of the PKA inhibitor KT5720 (2. PKC. There was a late increase of c-fos levels which accompanied the second PKA/CREB-P peak. 1996. 1997a. the PKC cascade extends for about 120 min. The second ‘‘wave’’ of PKA and CREB-P is also coincident in time AID NLM 3799 / 6v12$$$$63 10-21-97 23:52:05 nlmoal AP: NLM . Huang & Kandel. Both CREPP peaks correlate with those of increased PKA activity in the hippocampus (Fig. 1997b) and Bevilaqua et al. (1996. (1997). and effect of posttraining infusion into CA1 of 8-Br-cAMP (1. cAMP levels rise slowly after training.. reached a peak at 180 min.b) (Fig. higher peak at 180–360 min. 3 to 6 h after training (Bernabeu et al. CA1 levels of cAMP measured by radioimmunoassay (gray squares). in two peaks: One.25 mg/side.b). or CaMKII.. the first immediately and the second several hours after training (Fig. immediately after training. 1993. The data point to a crucial role in memory consolidation of a cAMP/PKA/CREB-P cascade in CA1. 4.. solid triangles) on retention of the avoidance task. There were two peaks of PKA activity and CREB-P: the first 0 min after training. a major difference between the PKA cascade and those initiated by PKG. 4). the CaMKII cascade lasts little more than 60 min. Posttraining 8-Br-cAMP enhanced memory when given 180 or 360 min after training. accompanied by a c-fos increase. Kim. or 360 min after training. and returned to normal at 540 min. 1994. and another one. 180. as well as to an early posttraining involvement of PKA (presumably using endogenous ‘‘basal’’ cAMP levels) and CREB-P in this process. 1995. and a second.

CaMKII.. Mayford et al. CREB-P...e. no cfos changes were detected in striatum or thalamus (Bernabeu et al. Fig. 1996). and posterior parietal cortex. 4). & Faull. 1996). and glycoprotein synthesis (see below). a randomsequence oligodeoxynucleotide has no effect (Guzowski & McGaugh. Bliss & Collingridge. 1995. A recent experiment by Guzowski and McGaugh (1997) underlines the key importance of hippocampal CREB for the persistence of memory for more than 4 h (as had been shown for hippocampal LTP. and cAMP/PKA/CREB-P cascades are sequentially articulated in LTP (Baudry et al. coincident with the second peak of CREB-P. 1997). a short-lasting molecular event that sets the stage for the development of a later. 1995). The Significance of Posttraining Biochemical Events in the Hippocampus The early events (glutamate receptor activation. protein. 1993. 1994. preceded in those cases by a lower early (0 h) peak.. Robertson. Malinow. noradrenergic.. which are very similar to those of the various forms of LTP (Izquierdo & Medina. among other proteins (Ferrer et al. Deisseroth et al. 1996. etc. CA3. 1992. 1997. 1989) has been very heuristic over the years. 1996. 1994). Martin & Kandel. Matthies.. 1997. Huang et al. 1996. C-fos increases have been reported not only after LTP (Dragunow. Izquierdo et al. 1995. Maren & Baudry. Maren & Baudry. Several years ago. after a great variety of forms of stimulation (Kaczmarek. 1984. and 5HT1A receptors (see below). based upon pioneering findings of his group on two posttraining peaks of RNA. 1996. Izquierdo & Medina. inasmuch as they represent major pathways used by the hippocampus to generate long-lasting synaptic plasticity of a facilitatory type. 1993) and maintain glutamatergic transmission enhanced for at least 6 h. 1997. entorhinal cortex. 1996. Abraham. since it lasts several hours and is modulated by substances acting on dopaminergic. The administration of an oligodeoxynucleotide against CREB mRNA into rat hippocampus prior to training hinders memory of water maze learning measured 48. We did in fact observe an increase of c-fos levels 3–6 h after training in CA1 (Fig.. h after training. Izquierdo. sometimes very rapidly. 1997b. Goulding. 4).. 1989) but also.. one right after training and the other 5–8 h later. CREB-P induces synthesis of the transcription factor c-fos. 1992). Posttraining c-fos increases are seen in CA2. Mason. in particular. Huang et al. 1993. Reymann. 1995. and c-fos that occurs in the hippocampus after training is functionally more important than the first. AID NLM 3799 / 6v12$$$$63 10-21-97 23:52:05 nlmoal AP: NLM . but not 4. proteindependent phase of LTP. Matthies (1982.’’ long before CREB and its implications for plastic processes were discovered. because it led to the demonstration of the main steps involved in memory formation in the rat hippocampus (see above) and in other forms of plasticity both in the hippocampus and elsewhere (Carew. Lynch & Baudry... 1997. 1994. 1995. The postulation that memory may rely on LTP (Izquierdo et al. It is to be presumed that they subserve a similar role in the hippocampus in memory consolidation. i. 1989) elaborated on the possible function significance of these two metabolic ‘‘waves. It is possible that the second ‘‘wave’’ of PKA. Frey et al..297 HIPPOCAMPAL BIOCHEMISTRY AND MEMORY with the amnestic effect of intrahippocampal KT5720 (Bevilaqua et al. 1997b). PKC. The first ‘‘wave’’ of CREB-P and c-fos might be related to what Frey and Morris (1997) have recently defined as a ‘‘synaptic tag’’.) and the PKG. see Huang & Kandel.

1996. 1993. even likely. Huang et al. Carew.b.. from the prefrontal cortex. 1992.. Collingridge & Bliss. 1996). Bliss & Richter-Levin. the subiculum. 1989). Hyman. & Seidenbecher. even when successive LTPs were used in the same neuron field (Frey. Da Silva. RELATION OF HIPPOCAMPAL EVENTS WITH THOSE IN OTHER REGIONS OF THE BRAIN As mentioned above. medial septum. let alone when the effect of learning on LTP or vice versa was investigated (Barnes. repetitive aversive training may block CA1 LTP (Izaki & Arita. 1996.298 IZQUIERDO AND MEDINA Discussion of this issue. 1996).. GABAA receptor agonists. slight departures from these sequences (for example.. Dawe. 1995). Jerusalinsky et al. 1996). 1992. Izquierdo et al. 1992.. 1991. some that are and others that are not regulated by retrograde synaptic messengers. Witter. some whose late proteindependent phase is modulated by D1 receptors and others in which this phase is modulated by b-adrenoceptors. Malinow. & Voronin. 1992. it is wise to simply admit that the biochemical events of memory formation in rat hippocampus are very much like those of LTP (Bernabeu et al. 1997. 1–4) and to refrain from proposing causal relationships between the two sets of phenomena. In the hippocampus or cerebellum. Stephenson. van Hoesen & Damasio. Nicoll & Malenka. Willner.b. Figs. Jerusalinsky. 1993.. some that need and others that do not need the activation of metabotropic receptors. That there may in many cases be an overlap. 1995... Bueno e Silva. has now become a bit idle (Barnes. Murphy. Sokolov. 1995). Christofi. Huang & Kandel. These stimuli may or may not arrive in volleys such as are needed to provoke clear-cut. 1993. 1994.. including some that are NMDA-independent. the hippocampus is supposed to receive the stimuli relevant to the training experience from collaterals of the sensory system. etc. 1964. AID NLM 3799 / 6v12$$$$63 10-21-97 23:52:05 nlmoal AP: NLM . 1993. At this stage. 1995. Quillfeldt. 1996). Bevilaqua et al. 1996. 1996). and PKC or CaMKII inhibitors (Davis. & Izquierdo. and entorhinal cortex: Early sensitivity to NMDA and AMPA receptor blockers. 1997. that the hippocampus will use biochemical sequences similar to those of one or another type of LTP depending on the task and on the subarea that plays a primary role (CA3 or CA1. 1996. long-lasting LTP (Bliss & Collingridge. Yin & Tully. 1997. It is possible. Reymann. etc. a predominance of phosphatase over CaMKII activity) generate instead long-lasting depression (Bindman. Rose. In learning situations. Tsumoto. 1993).. Bianchin. (Bliss & Collingridge. as other systems do (see Bartsch et al. 1994). However. Green. Walz. Zanatta. 1995. Izquierdo et al. 1990. however. 1995a. Bueno e Silva. Lopes da Silva. 1997a. and from the entorhinal cortex (Damasio. is the least that can be expected from processes that share the same cell population and many of the same mechanisms. Davis et al. & Nowicki. 1997.. 1996. It should be expected that in most situations in which the hippocampus is required to maintain synaptic function enhanced for a long time it will use similar biochemical processes. many such ‘‘saturation’’ studies have failed (see Barnes. Carew. There are now many known types of LTP. Izquierdo & Medina. 1993). Groenewegen. Walz. Kleschevnikov. Kuhnt. and. for example. Schollmeier. 1995. cholinergic muscarinic and noradrenergic agonists and antagonists. 1995. some of the early events of memory formation in the hippocampus also occur in amygdala. Mayford et al. & Lohman. see Gabrielli et al. some that involve presynaptic changes more than others.

Zanatta. & Salinas. like habituation to a novel environment. This should not be surprising. 1997). Schmitz. Quevado. & Izquierdo. and 60 min after training in posterior parietal cortex.. 1992. 1990). cholinergic nicotinic receptors. & Medina. Kajiwara. McGaugh.. vasopressin. This phase extends for a few minutes after training in hippocampus and amygdala. 1993. as it does in inhibitory avoidance (Wolfman et al. 1992. 1992. 1991). Roo- AID NLM 3799 / 6v12$$$$64 10-21-97 23:52:05 nlmoal AP: NLM . given the direct synaptic connection between CA3 and CA1 (Hyman et al. and parietal cortex is sequential. Schmitz. Coleman-Mesches. muscimol-dependent phase of memory in hippocampus (and amygdala). in addition. Izquierdo et al.. Wolfman et al. Ruschel. 1996).. Cahill.. (1990) and Witter et al. Schmitz.. 1994a. The possible pathways involved should be searched for among those reviewed by Hyman et al.. 1995. 1989). entorhinal... Involvement of these areas depends on the task. Wolfman et al. and glucose (see Bohus. Quillfeldt. McGaugh. The late cAMP/PKA-dependent phase is absent in the amygdala (Bevilaqua et al. Schaeffer. Zanatta. 1994a. 1994). Jerusalinsky et al. 1995. Reymann. 1997a. serotonin. Zanatta.. which indicates that these structures operate sequentially and concertedly in the formation of memories (Izquierdo. Medina. 1995. & Matsumoto. (1989).299 HIPPOCAMPAL BIOCHEMISTRY AND MEMORY Bianchin. 1994a) that short or abortive forms of LTP-like phenomena (Bliss & Collingridge. The timing of the onset of the initial NMDA-dependent. but some have been observed in other hippocampal subareas as well (see above). oxytocin. Ichikawa. the amygdala plays a major role (Davis. 1996. In addition to its late role in memory processing. Izquierdo & Medina. Mesches. Medina. 1997. Brioni. Witter et al. 1997. 1991. Izquierdo. 1992) and apparently this role includes CaMKII (Mayford et al. epinephrine. Parent. in a highly emotional task (conditioned fear). Izquierdo. 1996). other data point to an early intervention of the entorhinal cortex in learning.. 1993. 1964. Quevedo. It is possible (Jerusalinsky et al. norepinephrine. 1997a) modulated by endogenous benzodiazepine-like substances (Izquierdo & Medina. Iijima.. 1992. as a station through which signals eventually reach the hippocampus so that this can play its role in consolidation (Squire. 1993. Schaeffer. 1994. 1991) and are. 1995. but lasts up to 270 min in the entorhinal or parietal cortex (Zanatta et al. Tominaga. In inhibitory avoidance all of them are necessary.. MODULATORY INFLUENCES IN THE IMMEDIATE POSTTRAINING PERIOD The early events (õ30 min after training) are subject to inhibition by GABAA receptors (Brioni. Witter. Most of the biochemical changes listed above have been observed in CA1. and the diverse indirect connections that exist among the various hippocampal subregions (Green. starts 30 min after training in entorhinal cortex. 1993) may participate in early posttraining memory processing by the amygdala or medial septum. 1992). Quillfeldt. 1993). glucocorticoids. the amygdala and the septum are not involved (Izquierdo et al. Paczko.. 1991. 1989.. in less emotional tasks. & Izquierdo. Wolfman et al. adrenocorticotropin. 1989. A variety of central and peripheral modulatory systems also influence memory in the early posttraining period: b-Endorphin. Gold. The time in which memory is sensitive to the amnestic effect of AP5 or muscimol is less than 30 min in hippocampus or amygdala. Izquierdo & Medina. Willner et al. modulated by cholinergic muscarinic and b-noradrenergic synapses (Izquierdo et al. 1994). 1996).

& Driscoll. Izquierdo et al. 1977. 1997). McGaugh. 1995. Ratka... 1991). 1995). 1989).. Peripherally administered catecholamines influence central catecholamine levels and actions (Gold. 1994. 1995. 1986). corticosteroids. most current evidence indicates that the amygdala is not a site of storage (Bevilaqua et al. 1989). Izquierdo et al.. 1997). Some evidence suggests that the medial septum/diagonal band complex may play a similar role (see Cahill & McGaugh. Their main influence on the hippocampal mechanisms of memory formation is therefore indirect and must consist of interferences with direct or indirect amygdala– hippocampus connections (Hyman et al. 1995. and opioid agonists and antagonists influence brain norepinephrine effects (see Izquierdo. Corticosterone also modulates memory consolidation of inhibitory avoidance in the chick (Rose. 1995. which signifies that many or most memories are actually formed and often retrieved while under their influence (Izquierdo. Rogan & Le Doux. Gallagher. 1997. 1989. Wolfman et al. McGaugh et al. Kapp. 1992. Clark. 1990. Calder. Paczko. 1997.. 1997. Rosenfeld. Juler.g. 1995).. 1997. Gray. 1989). 1997). 1997.. 1988. 1989. 1996. Ruschel. McGaugh et al. vasopressin and corticotropin influence brain catecholamine levels (see Bohus. McGaugh & Cahill. The same may be said of the medial septum/diagonal band area. 1997. Introini-Collison. This structure is believed to influence memory through its direct connection with the hippocampus (Izquierdo & Medina.. 1977.or phylogeny. 1989. Adolphs. Zanatta. and corticotropin. Witter et al. McGaugh et al. Despite earlier claims (e. Gold. Most of these substances are in fact released during many forms of behavioral training. 1997). Catecholamines enhance cAMP levels and thereby protein kinase A activity (Bevilaqua et al. Scott. 1997a. 1982). and hyperglycemia mimics the memory-facilitatory effects of these substances and enhances hippocampal LTP (Gold. Young. Izquierdo.300 IZQUIERDO AND MEDINA zendaal & McGaugh.. Garcia. Izquierdo et al. & King. 1993). Hormones and neuromodulators have been proposed to alter memory by AID NLM 3799 / 6v12$$$$64 10-21-97 23:52:05 nlmoal AP: NLM . Da Silva. & Thompson. & Johnson. Joe¨ls. & Izquierdo. Cahill & McGaugh.. Throughout onto. Harlan. for references). and alter protein kinase C activity (see Jerusalinsky et al. McGaugh et al... 1982. 1989) early after training.. 1995). Van Eekelen. Bueno e Silva. It is generally agreed that the amygdala is the main brain center that adds emotional ‘‘colors’’ or ‘‘tinges’’ to memories at the time of encoding (Cahill & McGaugh.. and corticoids regulate glycemia.. 1997). activate the phosphoinositide cascade. & Damasio. and this connection has a timelimited role in memory formation (Kim. 1996). 1996. 1995a). Cholinergic muscarinic agents upregulate NMDA receptors. the corticomedial prefrontal cortex may take over some of these functions (Damasio. Walz. McGaugh et al. Rockland. Peripherally administered opioids and opioid antagonists alter memory also partly through actions on the medial septum (Bostock. which is of course directly linked to the hippocampus (Gray. Musty. 1995). All these substances affect hippocampal LTP (see Gold. 1995) and at the time of retrieval (see Bechara. & Izquierdo. Heimer. see below). McGaugh & Cahill. Gallagher. McGaugh. Bianchin.. Hellawell. Alheid. Izquierdo. norepinephrine. Damasio. 1995. Glucocorticoids may also act through specific receptors in hippocampus (De Kloet. Gallagher et al. & De Olmos. 1996. 1995. 1996. 1996). & Levine. Peripheral epinephrine. 1995. Medina. McGaugh & Cahill. Aggleton. Izquierdo & Medina. Tranel. Most of these agents act primarily through interactions with brain noradrenergic mechanisms in the amygdala (Cahill & McGaugh.

1994) and of CA3 LTP by b-noradrenergic receptors (Huang & Kandel. These findings indeed correlate with the increase of the levels of hippocampal cAMP (Bernabeu et al.0 h after training) are modulated by dopamine D1 .. facilitate learning and retrieval. depression. or 9) h after training strongly facilitates memory of the step-down task. and 5HT1A receptors (Bevilaqua et al. Willner. of posttraumatic stress disorder.b) commented on above (Fig. 5HT1A receptors downregulate the early phase of dentate gyrus LTP (Sakai & Tanaka. the memory disturbances seen in disorders of these systems (e. and serotoninergic pathways which are believed to play a key role in the regulation of mood and affect (see Heimer et al. 1991). Forskolin. 1991. 1993). 1995). b-noradrenergic. b-noradrenergic. 1996. corticotropin... and 5HT1A receptors to depress.. which should presumably follow a linear dose–response curve. Izquierdo & Chaves. and 5HT1A receptors in the hippocampus is very wide (ú3 h) (Bevilaqua et al. 1997. Parkinson’s disease. It is known that low to moderate levels of arousal. of the D1 antagonist SCH23390. Chronic stress has been repeatedly implicated in the genesis of depression (Post.. ú3 h) upregulation of CA1 LTP by dopamine D1 receptors (Huang et al. Chronic stress or repeated glucocorticoid release or administration damages hippocampal pyramidal cells (see McEwen & Sapolsky. whereas too high levels of arousal or anxiety have an impairing effect (see Gold.. Wolfman et al.5.5. Infusion 3 or 6 h after training of the PKA inhibitor KT5720 (Fig. Izquierdo & Chaves.. 1997).301 HIPPOCAMPAL BIOCHEMISTRY AND MEMORY direct influences on gene transcription (Sossin. Bevilaqua et al. parallel sensitivity to D1 .e.. AID NLM 3799 / 6v12$$$$64 10-21-97 23:52:05 nlmoal AP: NLM . 1997a. Willner.. or mild anxiety. 1996) may be related to alterations in the regulation of the late phase of memory formation. epinephrine. 4). However. McGaugh et al. The role of brain benzodiazepine-like substances in memory modulation may be related to the regulation of anxiety or stress (Izquierdo & Medina. 1996. or of the 5HT1A antagonist NAN-190 3 or 6 (but not 0. noradrenergic. 1995). and catecholamine releasers facilitate memory at low doses but impair memory at high doses (Gold. or 9) h after training (Bernabeu et al. D1 and b-noradrenergic receptors are known to stimulate. 1995.0–6. 1996) and CREB-P (Bernabeu et al. 1990) and. Thus. norepinephrine. 4). 1995. 1992. 1996). 1. of the b agonist norepinephrine. Recent unpublished findings from our laboratory suggest that a similar. 1996). 1997).. glucocorticoids.. of the b antagonist timolol. Infusion into CA1 of the D1 agonist SKF38393.. adenylyl cyclase activity. Dopamine D1 . schizophrenia. 1997.g. Izquierdo. and 5HT1A receptors are of course activated by the dopaminergic. This argues against a direct role on gene transcription. for references). b-noradrenergic. MODULATORY INFLUENCES 3 TO 6 H AFTER TRAINING In the rat. of course. 1990). Their late modulation of memory seems indeed linked to these effects. 0. 1989. or of the 5HT1A antagonist 5-HODPAT is instead strongly amnestic. both of which have profound cognitive influences. 4). Fig. It must be noted that the late time window during which memory formation is exposed to the influence of dopamine D1 . and 8-Br-cAMP itself enhance memory when infused into CA1 3 or 6 (but not 0. the late events in the hippocampus (3. vasopressin. another adenylyl cyclase activator. They also agree with findings from Kandel’s group of a late (i. Korneyev (1997) has proposed that memory-related effects of anxiolytic drugs may be mediated by influences on the hypothalamic–pituitary–adrenocortical axis.

& Steele. Squire. 1992). emotional or affective components (Bohus. 1995b). 1995a). 1995. 1997). the data show early upregulation of NMDA receptors in the IMHV (Stewart. Sullivan. ROLE OF THE HIPPOCAMPUS AND OTHER STRUCTURES IN RETRIEVAL The involvement of the hippocampus in many if not all forms of declarative memory has been known for a long time (Barnes. The sequential participation of the hippocampus. Izquierdo & Medina. & Ackerman. pertaining to alerting.’’ to the memories. Green. 1995).. Eichenbaum. 1994. 1995). ‘‘colors’’ or ‘‘tinges. Clegg. the biochemical cascades in a given set of synapses in the hippocampus may change depending on direct or indirect influences of the various neuromodulators and hormones on this structure (Izquierdo & Medina. 1995b). increased CaMKII activity (Zhao et al. 1996). 1985. another at the time of memory formation. During acquisition it must receive information from the working memory/ AID NLM 3799 / 6v12$$$$64 10-21-97 23:52:05 nlmoal AP: NLM .302 IZQUIERDO AND MEDINA b and 5HT1A receptors. and another at the time of retrieval.. early phosphorylation of GAP-43 coupled with increased PKC activity (Bourchuladze et al. and both an early and a late activation of early genes. Further.. by directly affecting the biochemical processes of memory. 1990). 1991. 1996. 1985. 1997). Dopaminergic. 1992. forskolin. where the IMHV and the LPO enter into play sequentially after training in inhibitory avoidance (Rose. 1992. In other words. an amnestic effect of NMDA receptor antagonists (Bourchuladze & Rose. 1992). 1996. The cognitive influence of mood. signaled by increases of cfos and c-jun (Anokhin et al. 1995).. A major difference between the biochemical changes reported in hippocampus and those found in the chick brain is the apparent lack of participation of AMPA receptors in the latter (Bourchuladze & Rose. 1992). 1979. Bourne. The hippocampus forms part of three related but different circuits: One at the time of acquisition. 1996. and important. Milner. and emotion has been known for years (see below and Bohus. 1995a. Rogan & Le Doux. Cohen. and serotoninergic systems. 1991. 1991). Barnes & McNaughton. Izquierdo & Medina.b). 1997). entorhinal cortex. Corkin.. adding components (Izquierdo et al. 1994. 1970. and 8-Br-cAMP exists in the entorhinal cortex in relation to memory (see Bevilaqua et al. similarities between posttraining biochemical events in rat hippocampus and in chick brain exist at the level of late changes in synaptic glycoproteins (see below). Cahill & McGaugh. 1964. 1995. Corticosteroid modulation of memory formation in the chick brain has been attributed to an influence on the late synthesis of glycoproteins (Rose. Rosen. SIMILAR BIOCHEMICAL EVENTS IN CHICK BRAIN Many of the biochemical steps described above have been also observed in the intermediate medial hyperstriatum ventrale (IMHV) and in the lobus paraolfactorius (LPO) of the chick brain after another form of inhibitory avoidance (not to peck a bitter bead) (Rose. and parietal cortex in memory consolidation in rats is remindful of what happens in the chick. an early role for metabotropic receptors (Rickard & Ng. introduce information of their own. affect. Rose. Izquierdo & Medina. noradrenergic. In the chick.

occipital) also participate in AID NLM 3799 / 6v12$$$$64 10-21-97 23:52:05 nlmoal AP: NLM . 1985. Scott et al. 1997a. Schmitz. pretest CNQX has no effect on retention test performance when given into the entorhinal cortex. 1997a) and fits with clinical data on the limited duration of the retrograde amnesia of patients with medial bilateral lesions of the temporal lobe (Corkin et al. Schaeffer.. Their role requires AMPA receptors: CNQX infused prior to testing into any of these structures causes a transient block of memory expression.. 1993). Quevado. Thirty days after training. Possibly. It is interesting that the sequence by which these four structures enter into plays in the process of memory formation is the same in which they disappear from the stage at the time of retrieval. Zanatta et al. Medina. This indicates that.. This also indicates that the control of memory expression is transferred to the entorhinal and the posterior parietal cortex at 30 days from training (Izquierdo et al... Willner et al. cingulate. Quillfeldt et al. Zanatta et al. 1995). the posterior parietal cortex still holds control over memory expression (Izquierdo et al. 1996). the hippocampus and amygdala integrate a network with the entorhinal and parietal cortex. in the first few days after training.. In humans. & Izquierdo. pretest CNQX given into the hippocampus and amygdala is no longer effective. 1992) and. 1997). 1996) (see above). 1995). In the posttraining period of inhibitory avoidance. some evidence suggests that the emotional functions of the latter could be taken over by the corticomedial prefrontal cortex (Damasio. Quillfeldt.g. 1989). then entorhinal cortex. Bianchin et al. Acquisition is not the concern of the present article. but it still hinders retrieval when infused into the entorhinal or posterior parietal cortex (Izquierdo et al. 1996). for example. which is related by the entorhinal cortex and the dentate gyrus (Hyman et al. with the entorhinal and parietal cortex (Izquierdo et al. 1970).. 1997a.. the amygdala. Preliminary findings from this laboratory show that 90 days after training the effect of pretest CNQX given into the parietal cortex is only partial.. by that time. and finally parietal cortex (Izquierdo et al. but it is amnestic when infused into the parietal area..’’ At the time of retrieval. 30 to 60 min later. It remains to be seen whether other areas of the brain take over the role of the amygdala (see above) or of the hippocampus and entorhinal cortex at 2 months from the original training experience.. the hippocampus and amygdala are no longer necessary for retrieval.. 1996.. other cortical areas (frontal. 1996). some of them.. 1997a. although of course with a very different time course: First hippocampus and amygdala. in fact. Quillfeldt et al. 1993.. This does not necessarily mean that memories are stored in any of these structures... Brioni (1993) has considered the fact that the various findings on the simultaneous and coordinated activity in the posttraining period are evidence for ‘‘the multiple consolidation of memory. It just means that the structures are necessary for retrieval. the hippocampus operates concertedly with the amygdala and medial septum/diagonal band area (Izquierdo et al. This shows that.. as was erroneously interpreted some years ago (e. At 60 days from training. 1997a. possibly different hippocampal subregions participate in the encoding and retrieval of different tasks (Gabrielli et al. 1995. De Lima. 1997a). Milner. Witter et al. may be so in order to add emotional or aversive ‘‘tinges’’ to the memory at that time (see Bechara et al. Zanatta. 1990.HIPPOCAMPAL BIOCHEMISTRY AND MEMORY 303 manager regions of the prefrontal cortex (Fuster. 1997).. by that time. all of which are needed for retrieval (Izquierdo et al..

1988) and/or a loss (Wallha¨usser & Scheich. 1997). no doubt. 1997a. which can only be explained by extensive synaptic growth and rearrangement in the remaining brain tissue. Rose. Valenstein. 1996. 1985). (Bernabeu et al. 1980). & Spruijt. This precludes any idea that they may be synapse-specific. Jaffard. and all appear to be learningspecific (they are not seen in animals exposed to the footshock alone or to the apparatus without the footshock). 1995). may in many cases rely on anatomically visible changes. and Rosenzweig (1964) reported pronounced changes in brain weight and protein content in rats raised in an enriched environment. Bowers. shortening (Brandon & Coss. 1996. Krech. heme oxygenase. Three decades ago. if they preferentially affect the synapses that are being activated at the time. early in this century. instead. other aspects of spatial and nonspatial declarative learning involve the striatum (Packard & McGaugh. Hwang. Gispen. 40–80% increases in CREB-P. 1995a. or after fornix lesions in rats (van Rijzingen. despite the fact that inhibitory avoidance. 1995. Diamond. they are. 1997) (Figs. several-fold increases of cGMP and cAMP. The need for the suppression of some behaviors in order to permit the acquisition and storage of new ones using the same brain systems is not given the attention it deserves. structurespecific (they are not seen in other brain regions). or CaMKII. by description. etc. including clinical and experimental observations on the recovery of function after hemispherectomy at an early age (see Izquierdo. but must involve long-lasting functional alterations that make some synapses more efficient and. however. involves precisely this (Netto & Izquierdo. cellular changes seen over the whole hippocampus or entire subregions of the hippocampus. PKA. PKC. Functional synaptic alterations. Good. was the first to propose that morphological changes underlie plastic phenomena in synapses. Common sense dictates that long-term memory storage does not rely on the production of new proteins or other molecules. Verfaellie.. others less efficient (Dunn. 1–4). & Destrade. Some of the biochemical changes are. Some aspects of spatial learning involve non-NMDA-mediated mechanisms. PKG.. Many studies in animals and in rats have borne out these seminal findings. & Morris.b. probably in the hippocampus (Bannerman. 1987). Several data suggest that many of these changes are indeed activity-dependent (see Izquierdo & Medina. Ramsay. Some consequences of the biochemical changes. 1995. 1987) of dendritic spines or other components of synapses have been observed in the hippocampus and elsewhere a few hours after brief train- AID NLM 3799 / 6v12$$$$65 10-21-97 23:52:05 nlmoal AP: NLM . 1997. 1996. 20–80% increases in AMPA binding or in the amount of measurable GluR1 or NMDA1. and an increase in number (Patel & Stewart. perhaps. & Gorman. Ramo´n y Cajal (1952). Day. Bennett. 1985). Heilman. Growth (Greenough. 1982). & Watson. Cammarota et al. 1997). Butcher. like those that occur during brain development.304 IZQUIERDO AND MEDINA long-term storage (Bontempi. 1992).b). THE CONNECTION BETWEEN POPSTRAINING HIPPOCAMPAL EVENTS AND EFFECTIVE MEMORY CONSOLIDATION: CELL ADHESION AND SYNAPTIC GROWTH The biochemical changes seen in the hippocampus after inhibitory avoidance learning are very large: 20–120% increases of the activity of enzymes such as NO synthase. may well be synapse-specific.

For example. 1996. 1995a. 1992b) or into the chick brain (Scholey. Schachner. & Sara... Very recently. Pohle. 1997). 1993) and in the rat hippocampus (Doyle. Nolan. the cells group in well-defined ribbonlike clusters and present a large increase in spine numbers (O’Connell et al. It is interesting to note that the second ‘‘wave’’ of changes related to the glycoprotein matrix. and again 7 or 8 h later (Matthies. Mu¨ller. Geinisman. of course. if not most.5 h after training. Scholey. Activity-dependent changes in cell adhesion explain changes in synaptic function (Field & Itoh. but also a major site of projection from the hippocampus. but also when injected intracerebroventricularly into rats 5. Antibodies to these substances hinder memory of inhibitory avoidance when given before or 5. Mileusnic. 1994). & Matthies. As mentioned above. 1995). 1989). an antibody raised against chick forebrain NCAM is amnestic not only for inhibitory avoidance in the chick. Bell. 1987. A role for the GAP-43 protein in synaptic morphological changes has been suggested by Benowitz and Routtenberg (1997). c-fos synthesis. a 25. 1997. see above).. L1 and NCAMs have been attributed a regulatory role in the maintenance of hippocampal CA1 LTP (Field & Itoh. It is tempting to relate these changes to the biochemical events that occur in the hippocampus precisely at that time (CREB-P increase. & Regan. & Schachner. multiple partitioning of transmission zones in axospinous synapses of the hippocampus following repeated LTP. Witter et al. Laurent. see Field & Itoh. Rose. Bell. follows the cAMP/PKA/CREB-P/protein synthesis changes by 1 or 2 h. Rossi. Heller. Morrell. entorhinal cortex. 1982. & Schachner. (1997) has been ascribed to changes in cell adhesion factors. as are the amygdala. Przybyslawski. Nolan. we have recently shown PKC-mediated phosphorylation of hippocampal GAP-43 30 min after inhibitory avoidance training in the rat (Cammarota et al.5–8 h after training into the rat cerebral ventricles (Doyle. & Regan. Figurov. and septum (Hyman et al. Lu¨thi. 1997). The morphological changes seen in the dentate gyrus or elsewhere may also AID NLM 3799 / 6v12$$$$65 10-21-97 23:52:05 nlmoal AP: NLM . Importantly. Mileusnik. Rose.HIPPOCAMPAL BIOCHEMISTRY AND MEMORY 305 ing experiences. forms of long-term plasticity (Benowitz & Routtenberg. Iijima et al. Rose. Such partitioning would escape notice unless very specific neuroanatomical methods are used. Bock. Zamani. 1990. It is very likely that more subtle changes in synaptic morphology may occur in many. Rose & Jork. 1996. not only an input link between the entorhinal cortex and the hippocampus proper. for inhibitory avoidance in the rat (Alexinsky. 1996. & Rose. de Toledo-Morrell. 1995a). 1982. 1979). and Parshall (1993) have described the development of complete. 1995a). 3). Fig. such as the L1 and the neural cell adhesion molecules (NCAMs). 1995a). in both hippocampus and neocortex: Early after training. which is coherent with the idea that they may be a consequence of the latter (Matthies. Popov. The dentate gyrus is. Ru¨thrich. Glycoproteins in the external side of cell membranes play a major role in this (Rose. 1992a) following different forms of one-trial inhibitory avoidance training. 1996.. or in some cases synaptic morphologic changes. 1997).to 30-fold increase in hyperchromic granule cells (toluidine blue staining) has been observed 5 to 7 h after inhibitory avoidance training in the adult rat hippocampus. 1989.. Rose. The enhanced clustering of hyperchromic dentate granule cells 5 or 7 h after inhibitory avoidance shown by O’Connell et al. Increased fucose uptake occurs in two ‘‘waves’’ after brightness discrimination training. Two similarly spaced ‘‘waves’’ of sensitivity to the amnestic effect of locally injected antagonists of terminal fucosylation of glycoproteins have been described in the chick brain (Rose.

alongside with CREB. A variety of such pathways exists (Nieuˇwenhuys. During LTP and other forms of enhanced electrical activity tPA is induced through an NMDA-receptor-mediated mechanism in rat hippocampus as an immediate early gene (Qian. AN ACTIVE LOOP BETWEEN THE HIPPOCAMPUS AND MODULATORY SYSTEMS One point deserves comment as a possible source of further study. CONCLUSION AND A WORKING HYPOTHESIS To summarize. 3–6 h later. Witter et al. there must be hippocampofugal pathways that inform the substantia nigra. the message back from these areas to the hippocampus (but not the amygdala) is quite clear. Izquierdo et al. 1979.. Colicos. see above). Therefore. 1989). noradrenergic. Gilbert.. Activation of dopaminergic. the locus coeruleus.. and the other. 1993). instruct the hippocampus to produce more cAMP and so activate the PKA/CREB-P pathway. Each of these ‘‘waves’’ is followed by changes in glycoprotein synthesis and by events that may be explained by changes in cell adhesion. 1985) and where interference with the expression of AMPA receptors at the time of testing also hinders retrieval for a few weeks (Bianchin et al. and serotoninergic pathways around 3 h after training appears to occur physiologically: The blockers SKF 23390. For memories persisting more than a few weeks in whose retrieval cortical structures other than the hippocampus play a role (entorhinal cortex.e. i. Two pathways. Quillfeldt et al. and 5HT1A receptors on adenylyl cyclase. such as activity-dependent synaptic adhesion changes mediated by glycoproteins. the sites where the cell bodies of the brain dopaminergic. where LTPs lasting for several weeks have indeed been described (Barnes.b). timolol. On the basis of the known influence of D1 . & Kuhl. followed by morphological changes (Rose. and serotoninergic systems are (Nieuˇwenhuys. There is no evidence that memory is stored in the form of LTP. 1997). particularly the second ‘‘wave. There are two ‘‘waves’’ in this chain: One right after training. and save the learned information. induce protein synthesis. noradrenergic. etc. the one ending on D1 receptors and the one ending on b-adrenoceptors.. 1985. certainly it might be wiser to think of mechanisms different from LTP. posterior parietal cortex. 1996).’’ It is likely that the second wave is triggered by the reflex activation of noradrenergic and AID NLM 3799 / 6v12$$$$65 10-21-97 23:52:05 nlmoal AP: NLM . 1997a. 1996). the prolongation of LTP beyond 4 h in CA1 (Frey. and NAN-190 had powerful actions on their own when infused into the hippocampus but not the amygdala at that time or later (Bevilaqua et al. 1985). 1995a. 1993.. which apparently supports. Kandel. The release of tPA is linked to morphological differentiation and may correlate with activity-dependent morphological changes (see above). in the first 6 h after training there is a chain of biochemical events in the hippocampus that is necessary for memory processing. This could be a possibility in the case of the hippocampus. both related to cAMP-sensitive gene transcription. that a learning situation has taken place 3 h before. The pathway that innervates the 5HT1A receptors obviously gives a contrary message. b. and the raphe nuclei... Barnes & McNaughton. Mu¨ller. & Kuhl.306 IZQUIERDO AND MEDINA be related to expression of the gene for extracellular serine protease tissue plasminogen activator (tPA).

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