Neuron, Vol. 15, 1053-1063, November, 1995, Copyright © 1995 by Cell Press
Bidirectional Synaptic Plasticity Inducedby a Single Burst during CholinergicTheta Oscillation in CA1 In Vitro
Patricio T. Huerta* and John E. Lisman
Center for Complex SystemsDepartment of BiologyBrandeis UniversityWaltham, Massachusetts 02254
SummaryIn standard protocols, the frequency of synaptic stimu-lation determines whether CA1 hippocampal synapsesundergo long-term potentiation or depression. Herewe show that during cholinergically induced theta os-cillation (e) synaptic plasticity is greatly sensitized andcan be induced by a single burst (4 pulses, 100 Hz).A burst given at the peak of e induces homosynapticLTP; the same burst at a trough induces homosynapticLTD of previously potentiated synapses. Heterosynap-tic LTD is produced at inactive synapses when othersundergo LTP. The synaptic modifications during e re°quire NMDA receptors and muscarinic receptors. Theenhancement is cooperative and occludes with stan-dard LTP. These results suggest that the similar burstsobserved during 0 rhythm in vivo may be a naturalstimulus for inducing LTP/LTD.Introduction
Long-term potentiation (LTP) and long-term depression(LTD) are activity-dependent forms of synaptic plasticitythought to underlie memory formation in brain regionssuch as the hippocampus and the neocortex. The prevail-ing view is that these processes are triggered by stimula-tion patterns of markedly different frequencies (Artola andSinger, 1993; Linden, 1994; Teyler et al., 1994). Typically,LTP is induced by 1 s of high frequency (100 Hz) stimula-tion (Bliss and Lemo, 1973; Bliss and Collingridge, 1993),whereas LTD is produced by 7-15 min of low frequency(1-3 Hz) stimulation (Dudek and Bear, 1992; Mulkey andMalenka, 1992).It is unclear whether spike trains similar to the patternsused for LTP and LTD induction occur during brain func-tion and, consequently, whether they represent the naturaltrigger for synaptic plasticity. Regarding LTP induction,high frequency spiking does occur in the hippocampus(Buzsaki, 1986; Ylinen et al., 1995a), but it is unlikely thata given pyramidal neuron fires for a full second becauseof spike frequency adaptation. A common pattern of hippo-campal activity is repetitive, brief bursts (i.e., 2-7 spikesat 100-200 Hz) at theta-frequency (5-12 Hz; e.g., Otto etal., 1991). It has been shown that 10 such bursts deliveredevery 200 ms seem particularly suited for inducing LTP,*Present Address: Center or Learningand Memory/HowardHughesMedical nstitute, Massachusetts nstituteof Technology,Cambridge,Massachusetts, 02139.both in vitro (Larson et al., 1986) and in vivo (St&ubli andLynch, 1987). However, it remains unclear whether sucha repetitive bursting occurs naturally for a sufficient time(O'Keefe and Recce, 1993). Some in vitro work has shownthat a few bursts are able to produce synaptic potentiation,but the potentiation is small (Rose and Dunwiddie, 1986;Diamond et al., 1988), is short-lasting, and requires re-moval of GABA-mediated inhibition to be obtained (Wigs-trSm and Gustafsson, 1985; Gustafsson et al., 1987;Hanse and Gustafsson, 1992). There is thus no clear indi-cation that a pattern of activity capable of producing robustLTP in vitro actually occurs in the brain.The type of stimulation required for LTD induction iseven more problematical. Theoretical work in neural net-works has shown that simple rules for synaptic plasticitycan lead to the storage of multiple memories in the samenetwork, provided that the modifications are bidirectional(Willshaw and Dayan, 1990; Hertz et al., 1991). This pre-vents synapses from becoming saturated, and it is vitalfor proper network function. In these models, activity-dependent weakening occurs whenever presynaptic andpostsynaptic spikes are not correlated. Generally, it hasbeen assumed that similar weakening exists at brain syn-apses and that LTD is a prototype. However, the synapticweakening incorporated into nerve net models occurs witheach noncorrelated spike at a time scale of milliseconds,whereas LTD is induced experimentally by a stimulationprotocol lasting many minutes. Furthermore, synapse-specific LTD requires that specific spatial patterns of lowfrequency activity are maintained for minutes, but thereis no evidence for such prolonged persistence in vivo. Infact, it is thought that low frequency firing in the brain isprimarily noise.The induction patterns for LTP and LTD describedabove may only be necessary in vitro because of the lossof ascending modulatory inputs to the hippocampus. Itis well established that hippocampal function is stronglyinfluenced by modulators arising from subcortical struc-tures. In particular, the cholinergic system that originatesin the medial septum and diagonal band of Broca, andinnervates the whole hippocampal formation, is known toenhance synaptic plasticity (Ito et al., 1988; Hasselmo andBower, 1993; Huerta and Lisman, 1993; Auerbach andSegal, 1994). A low dose of cholinergic agonist producesa modest enhancement of the magnitude of LTP (Burgardand Sarvey, 1990; Maeda et al., 1993). Higher dose ofcholinergic agonist induces a network oscillation in thetheta-frequency range (henceforth termed e; Konopackiet al., 1987; Bland and Colom, 1993), and under theseconditions synaptic plasticity is dramatically sensitized(Huerta and Lisman, 1993). Specifically, 40 single shocksat 0.1 Hz, which would ordinarily produce no potentiation,elicit synapse-specific LTP if each shock is delivered atthe peak of a e wave. The ease of producing synapticmodification during 8 led us to ask whether LTP and LTDcould be triggered in vitro by a very brief burst (4 shocks
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