Rev. Neurosci.

2015; 26(3): 253–268

Zareen Amtul* and Atta-ur-Rahman

Neural plasticity and memory: molecular

mechanism
Abstract: Deciphering the cellular and molecular mecha- Introduction
nisms of memory has been an important topic encom-
passing the learning and memory domain besides the
The encoding, storage, and retrieval of memory result
neurodegenerative disorders. Synapses accumulate cog-
from the coordinated activity and interaction of millions
nitive information from life-lasting alterations of their
of neurons and synapses in the brain. A change in this
molecular and structural composition. Current memory
interactive efficiency of neuronal or synaptic signaling,
storage models identify posttranslational modification
also known as plasticity, is a critical characteristic of com-
imperative for short-term information storage and mRNA
munication among synapses and neurons. For instance,
translation for long-term information storage. However,
Hebbian forms of long-lasting synaptic plasticity, that
the precise account of these modifications has not been
is, long-term potentiation (LTP) (Hebb, 1949) and long-
summarized at the individual synapse level. Therefore,
term depression, are well documented and considered
herein we describe the spatiotemporal reorganization of
to form the molecular basis for certain types of memory.
synaptic plasticity at the dendritic spine level to elucidate
LTP is also explained an electrophysiological event with
the mechanism through which synaptic substructures are
an increase in postsynaptic potentials after synapse teta-
remodeled; though at the molecular level, such mecha-
nization. It is considered to ensure long-term alterations
nisms are still quite unclear. It has thus been concluded
in synaptic efficacy in distributed networks, leading to
that the existing mechanisms do not entirely elaborate
persistent changes in the choices, actions, and behavioral
memory storage processes. Further efforts are therefore
patterns, which are often interpreted as the retention of
encouraged to delineate the mechanism of neuronal con-
information, that is, memory. These alterations, however,
nectivity at the chemical level as well, including inter- or
have not been explained at the individual synapse level.
intramolecular bonding patterns at the synaptic level,
This review highlights recent work on molecular and
which may be a permissive and vital step of memory
structural events specifying the alterations in short- and
storage.
long-term synaptic plasticity and memory development.
Based on different conceptual and methodological
Keywords: learning; long-term potentiation; memory
advances, we propose to reconsider the synapse as a hard-
encoding; synapse; synaptic plasticity.
wired element built for fast electrochemical transmission,
which has a function tightly linked to the dynamic organi-
DOI 10.1515/revneuro-2014-0075 zation of hydrogen binding patterns (reviewed by Amtul
Received November 6, 2014; accepted December 14, 2014; previ- and Rahman, 2014).
ously published online March 3, 2015

*Corresponding author: Zareen Amtul, Division of Geriatric

Psychiatry, Department of Psychiatry, Schulich School of Medicine
Components of neural circuits
and Dentistry, Western University, London N6A 5W9, ON, Canada;
H. E. J. Research Institute of Chemistry, International Center for
or ensembles
Chemical and Biological Sciences, University of Karachi, Karachi
75270, Pakistan; and Dr. Panjwani Center for Molecular Medicine The brain gathers, manipulates, stores, and retries
and Drug Research, International Center for Chemical and Biological sensory perceptions as memory as well as classifies
Sciences, University of Karachi, Karachi 75270, Pakistan, encoded information. This remarkable ability of the brain
e-mail: zamtul@uwo.ca depends on the quantitative construction of a precisely
Atta-ur-Rahman: H. E. J. Research Institute of Chemistry, International
wired synaptic connection network (connectome) with
Center for Chemical and Biological Sciences, University of Karachi,
Karachi 75270, Pakistan; and Dr. Panjwani Center for Molecular
functional property of the synapses (synaptomes) (Frey
Medicine and Drug Research, International Center for Chemical and and Frey, 2008; Hernandez and Abel, 2008). Such data
Biological Sciences, University of Karachi, Karachi 75270, Pakistan patterns or maps are constructed from the quantitative

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254      Z. Amtul and A. Rahman: Synaptic plasticity and memory

reckoning of molecular and functional diversity both at a Neural extracellular matrix

particular brain area and at the individual synapse level.
A neuron is encased in a complex, nonhomogeneous,
highly aqueous gel-like extracellular space or environ-
Memory centers in the brain
ment known as the neural extracellular matrix (nECM)
(Dityatev et  al., 2010). The nECM is a reticulum that is
Precisely wired brain circuits established by axons and
comprised of electron-rich moieties, polyanionic biopoly-
dendrites are targeted to precise sites on the surface of
mers, glycosaminoglycans, and various other proteins
particular neurons in specific brain areas or ensembles
(Scott, 1995). Electrical and chemical synapses, nodes
(reviewed by Williams et  al., 2010), which include the
of Ranvier, integrins and gap junctions help a neuron to
following:
make contacts with the surrounding nECM. nECM not
–– Medial temporal lobe and hippocampus: Declarative
only functions as a computational matrix but also pro-
or explicit memory for events and facts and for places,
vides structural support to the neuron (reviewed by Marx
objects, and people is targeted to the medial temporal
and Gilon, 2013). There is a significantly larger volume of
lobe circuitry and hippocampus. The hippocampus
nECM found in human brains compared with chimpanzee
is the brain subregion vital to establishing long-term
brains (Balter, 2007), indicating a greater learning compe-
episodic and spatial memory (Squire, 1992; Amtul
tency for higher cognitive activities.
et al., 2014a,b).
–– Cerebellum, striatum, and amygdala: In contrast to
the explicit memory, procedural or implicit memory
Elemental metals
for motor and perceptual skills is targeted to various
cerebral regions, including the cerebellum, the stria-
The homeostatic equilibrium in the levels of cerebral
tum, and the amygdala, depending on the type of the
metal ions is critical for neurotransmission, myelination,
skill. Simple reflex pathways are used in the most
mitochondrial function, various enzymatic activities, and
elementary instances.
learning and memory (reviewed by Duce and Bush, 2010).
–– Amygdala: Processed information from the neocor-
Neurons also release metal ions (Cu2+, Zn2+) containing
tex and direct auditory information from the thala-
vesicles. Trace monovalent metal cations, such as Rb+, Cs+,
mus are targeted to the amygdala, which is vital for
and Li+, are found in the brain at millimolar concentra-
both learned and instinctive fear (LeDoux, 1996). The
tions (with diffusion coefficients in the range of 13–21 × 10-6
amygdala synapses with the hypothalamus to regu-
cm2/s), whereas K+ and Na+ are found in high enough quan-
late autonomic fear responses. Experiments focused
tities to produce high intraneural voltage potentials. A great
on the amygdala provided the best evidence linking
majority of metals reside in the neural cells, a considerable
procedural fear memory to LTP (Moriya et al., 2000).
number (∼10%) are also found in the nECM (Scott, 1995).
Consolidation or reconsolidation (mechanisms that
Although the nECM allows free diffusion of some metals,
transform short-term memory into long-term memory)
others still require metal transporters, or metallothioneins.
of a reactivated declarative or procedural fear memory
Little is known about the process that helps neurons to
results in either protein synthesis or modification in
selectivity accumulate these elemental cations or their
the temporal lobe circuitry and amygdala, respectively.
redox activators (ascorbate, glutathione, etc.).

Neuron
Neuropil
A neural cell is the most important component of a neural
ensemble and capable of operating as an autonomous unit. A neuropil is a complex felt-like mesh formed by den-
It is closely linked to its surrounding using many superfi- drites, axons, and astroglial processes, where most of the
cial receptors, sensors, and electroeffectors. The number synaptic interactions occur.
of neurons in the human brain approximates the number
of stars in the galaxy. On average, one neuron is intimately
connected to its surrounding via 1000 contacts. The Organization of the neuropil
neurons also contain vesicles (loaded with neurotransmit-
ters, ions, and trace metals), released by nerve impulses The composition and structure of synapses may vary
(spikes or neuronal firing) called action potentials. during maturation, normal aging, development, trauma,

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and neurological disorders as well as across brain regions.
A deeper appreciation of their plasticity and structural
diversity may lead to novel insights into the processes that
govern the formation, maintenance, growth, and elimina-
tion of synapses. A transmission electron micrograph may
illustrate the following ultrastructural features of the neu-
ropil compartments (Figure 1):
–– Axonal boutons: Individual axons weaving through-
out the complex neuropil form presynaptic boutons
that contain neurotransmitter-filled vesicles. The
large majority (∼75%) of these vesicle-containing bou-
tons constitute a single synaptic contact, ∼21% form
multiple synapses, and ∼4% lack a postsynaptic part-
ner (Sorra et al., 2006).
Figure 1: A transmission electron micrograph of Golgi-impregnated
neuronal cell in the hippocampus illustrating the ultrastructural
features of the key physiologic neuropil compartments, soma and
apical and basal dendrites. The inset shows an axon passing by
dendritic spines protruding from the shaft of apical dendrites.
Image was adapted from Harris and Weinberg (2012), with permis-
sions from Cold Spring Harbor Laboratory Press © 2012, John
Wiley & Sons © 1959, and Elsevier © 1980.
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Z. Amtul and A. Rahman: Synaptic plasticity and memory      255
–– Synapses: Tens of thousands of synapses are richly
decorated on dendritic arbors that are usually extraor-
dinarily branched and travel hundreds of micrometers
away from the soma of most neurons. The synapse is an
incredibly complicated and deeply diverse structure,
mediating highly plastic signaling, spanning sensory/
presynaptic and motor/postsynaptic neurons, and
consisting of many diverse protein species expressed
by spanning parent neurons. The brain consists of
1010–1011 neural cells; each constituting upto 104 excit-
able synaptic contacts. This leads to an extraordinarily
intricate and highly developed network composed of
approximately 100 trillion (1014) synapses.
Classification of synapses
Initial studies of synaptic transmission classified syn-
apses into electrical synapses (where ions flow between
neurons through gap junctions of connexin proteins) and
chemical synapses (in which transmission is conducted
by neurotransmitters). In 1959, Gray identified two main
categories of chemical synapses based on their actions:
excitatory and inhibitory (Gray, 1959). Later on, the follow-
ing modulatory synapses were added to the list:
–– Excitatory or type I or asymmetric (later shown to be
glutamatergic) synapses: Excitatory synapses use glu-
tamate as the major neurotransmitter. For cognitive-
related plasticity, it is possibly the most significant
neurotransmitter system. Excitatory synapses are
primarily located on dendrites, dendritic spines, and
postsynaptic density (PSD) components. N-methyl
d-aspartate (NMDA) and α-amino-5-hydroxy-3-
methyl-4-isoxazole propionic acid (AMPA) ionotropic
receptors are the subtypes of glutamate receptors. The
AMPA receptors (AMPARs) are the main mediators of
basal synaptic transmission. Calcium (Ca2+) influx via
NMDA receptors (NMDARs) is central to the induction
of both LTP (Carasatorre and Ramirez-Amaya, 2013)
and long-term depression (LTD). The glutamatergic
transmission is considered a significant initial step
in the mechanisms underlying the formation of new
synapses, stabilizing synaptic contacts and structural
synaptic plasticity. For example, increased spine den-
sity observed in the hippocampus 24 h after trace eye
blink conditioning is blocked by NMDAR antagonists
(Leuner et al., 2003) (Figure 2A and B).
–– Inhibitory or type II or symmetric (later shown to
be GABAergic) synapses: Inhibitory synapses use
gamma-amino butyric acid (GABA) as the key neu-
rotransmitter. Inhibitory GABAergic synapses are
256      Z. Amtul and A. Rahman: Synaptic plasticity and memory

Figure 2: A schematic drawing showing an axon passing by dendritic spines, pre- and postsynaptic terminals (inset), molecular mechanism
for encoding LTP and LTD, and phenomenon of recall showing synaptic cleft, neurotransmitters, neurotransmitter receptors, ion channels,
vesicles, and stalk of axon. PKC, protein kinase C; NMDAR, N-methyl d-aspartate receptor; AMPAR, α-amino-5-hydroxy-3-methyl-4-isoxazole
propionic acid receptors; AC, adenylyl cyclase; PKA, protein kinase A; CaMKII, Ca2+/calmodulin-dependent kinase II; MAPK, mitogen-acti-
vated protein kinases; PKMζ, atypical PKC; EC, endocannabinoids; NO, nitric oxide; TrkB, tyrosine kinase B; mGluR, metabotropic glutamate
receptors; G, glutamate; BDNF, brain-derived neurotrophic factor. Image was modified from (Amtul and Rahman, 2014), reprinted with
permission from SAGE © 2014.

mainly located on axonal shafts and dendritic soma,
while a sparse distribution along both spiny and non-
spiny dendritic shafts is also noticed.
–– Synaptic proteins: Immunohistochemistry reveals
multiple isoforms of synaptic proteins (more than
3000; Filiou et  al., 2010), spanning deep intratype
molecular diversity between various regions of the
brain and types of neurons at the subcellular level.
This diversity includes both their distinct relative
expression levels and the distinct complement pro-
teins expressed. The activity record of a particular
synapse or network is built in the identity of its par-
ent pre- and postsynaptic neurons. Similarly, a pro-
tein primarily reflects the molecular architecture of its
synapse and the molecular signature to its parent neu-
rons’ identity. Importantly, such protein expression
diversity often appears to mirror functional diversity,
such as the plasticity, kinetics, and strength of synap-
tic transmission. Vesicular transporters, receptor sub-
units, adhesion molecules, scaffold, housekeeping,
and signaling proteins as well as molecules regarded
as neurodevelopmental cues are few members of the
rapidly growing lists of synaptic proteins.
–– Adhesion proteins: Current interest has shifted
toward mapping or encoding molecular markers that
form brain circuits and synaptic connections. Adhe-
sion proteins are well positioned to provide a code or
clue, also known as molecular signature, about the
identity of parent pre- and postsynaptic neural cells
as well as their connectivity pattern within the brain
circuit. Adhesion proteins participate in regulating
the development of specific neuronal circuits in the
developing brain. In the mature brain, a large number
of these molecules are retained at synapses (Arikkath

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and Reichardt, 2008; Sudhof, 2008). Ephrins and
immunoglobulin superfamily members (Dalva et al.,
2007) are important classes of adhesion proteins.
–– Synaptic vesicles: Presynaptic axonal boutons of
excitatory synapses contain round, clear transport
packets or vesicles (∼35 nm diameter; Qu et al., 2009)
loaded with at least 410 different proteins in synaptic
vesicles fractions (Takamori et al., 2006) and 200 in
clathrin-coated vesicles (McPherson, 2010). To load
the vesicles, the vesicle membrane is equipped with
ion pumps and neurotransmitter transporters for vesi-
cle delivery to the membrane (with docking and traf-
ficking proteins), to help endocytosis (with clathrin
and associated proteins), and to expedite exocytosis
(with priming proteins).
–– The presynaptic active zone: The presynaptic active
zone is equipped with molecular machinery to speed
up the release of synaptic vesicle to respond to Ca2+
influx. The cytomatrix electron-rich region close to the
neuronal membrane contains the proteins needed for
the exocytosis of vesicles, such as voltage-gated Ca2+
channels, actin signaling proteins, scaffold, cytoskel-
etal proteins, and proteins necessary for endocytosis.
A reliable estimate of the proteins found in this com-
partment is not available because of the difficulties in
isolating this component.
–– The synaptic cleft: A neurotransmitter is released from
a docked vesicle into the synaptic cleft. The synaptic
cleft is a tight junction where different cells contact one
another. In glutamatergic synapses, this specialized
site is precisely spaced around 25 nm apart with rigid
parallel membranes. The synaptic cleft is spanned by
more than 1000 isoform members of major adhesion
protein families (Zipursky and Sanes, 2010).
–– The PSD: PSD is rich in proteins responsible to
generate a response to neurotransmitter release.
Scaffold proteins stabilize the ion channels and neu-
rotransmitter receptors in the PSD membrane. Protein
kinases and signaling proteins (which modulate the
synaptic activity such as phosphatases) are found in
abundance in the PSD. At glutamatergic synapses,
PSD is rich in cytoskeleton proteins that extend into
the dendritic spines (small membrane protrusions
from dendritic shafts and the sites of excitatory input
of pyramidal neurons). From 200 to more than 1000
different proteins are found in PSD according to pro-
teomic studies (Dosemeci et al., 2007). The reduction
of PSD-95 was the initial noticeable alteration in syn-
aptic components. PSD-95 is a master regulator of the
anchoring and assembly of glutamate receptor subu-
nits, the PSD components.
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Z. Amtul and A. Rahman: Synaptic plasticity and memory      257
Synaptic plasticity or mutability
At present, synapses are considered exceptionally plastic
in composition, function, and architecture. The history of
self use-dependent plasticity, impulse traffic, homeosta-
sis, and modulatory effects or signals from neighboring
glial and neuronal cells strongly influence the synapses.
To study the experience-dependent plasticity, a pioneer-
ing work by Wiesel and Hubel stands as the primary
example. According to their findings, when one eye is
occluded early in development (to treat monocular dep-
rivation), a shift in the dominance of ocular neurons in
the cortex results. The cortical neurons activated by the
open eye are robustly increased in number, and time the
number of cortical cells that respond to the occluded eye
is reduced at the same (Wiesel and Hubel, 1963).
Synaptic plasticity and learning
Synaptic plasticity is elementary to learning and memory
development, remodeling, and homeostasis of complex
neural circuits. In the most widely accepted prevailing
paradigm of memory storage, learning-associated activity
modifies the strength of synaptic connections, communica-
tion, or transmission and subsequently render them stable
to persevere the memory trace (Mozzachiodi and Byrne,
2010). At the electrophysiological level, synaptic plasticity
is reflected in phenomena known as LTP and LTD.
Short-term synaptic plasticity
The initial perseverative activity is also called short-term
memory/facilitation or protein synthesis-independent
phase. Short-term plasticity (lasting up to 30 min) is
conducted by the continual covalent posttranslational
modification (PTM) of preexisting proteins of primarily
presynaptic sensory neuron (reviewed by Routtenberg and
Rekart, 2005). Short-term plasticity is sensitive to physical
interference. The application of electroconvulsive shock or
cooling (within seconds to minutes) after the acquisition
of information may result in the loss of short-term memory.
Long-term synaptic plasticity
The later consolidative phase is also called persistent
synaptic plasticity or long-term memory or protein syn-
thesis–dependent phase. The long-term synaptic plastic-
ity is characterized by the rapid transcription of mRNA
258      Z. Amtul and A. Rahman: Synaptic plasticity and memory

genes into proteins and the longer duration of ( ≥ 1 day of
the increased) synaptic efficiency. This gene transcription
and translation are required for newly growing synaptic
connections between the neural cells (Bailey and Chen,
1988a).
mechanism is also not completely known, although it
relies on both presynaptic and postsynaptic expression
mechanisms.
Spike timing-dependent plasticity

Types of long-term synaptic plasticity
LTP and LTD are two forms of long-term synaptic plasticity.
Long-term potentiation
According to spike timing-dependent plasticity, the polar-
ity of synaptic change is determined by the timing of pre-
synaptic and postsynaptic spikes (action potentials). LTP
results if a presynaptic action potential is followed by a
postsynaptic action potential repeatedly within approxi-
mately 50 ms, whereas the reverse order leads to LTD.

In LTP, repetitive presynaptic stimulation or synchronized

input (of 50 Hz, 100 Hz, or theta burst frequency, with
distinct mechanisms for each) (Kumar and Mehta, 2011) Molecular mechanism of synaptic
increases the sensitivity and strengthens postsynaptic
synapses. The notion that neurons that fire together and
plasticity or learning or LTP
wire together has been heavily influenced by the postulate
A variety of signaling molecules, receptors and enzymes
of Donald Hebb (1949), a Canadian neuropsychologist.
participate in the molecular underpinnings of LTP
LTP is also referred to as Hebbosomes (Husi et al., 2000)
(Figure 2). LTP offers enormous nearly indefinite compu-
or Hebbian plasticity. The meaning of Hebbian plasticity
tational capabilities (Gallister and King, 2009).
is that each experience we have regarding our thoughts,
sensations, feelings, and even muscle actions, is rooted in
the simultaneous activation of certain neuronal cells in a
Action potentials
network that generates that experience. Each time a spe-
cific thought (action) is repeated (synaptic tagging), the
The temporal sequence of electrophysiological action
connection between a group of neuronal cells is strength-
potentials or electrical activity was first observed in 1849,
ened. This phenomenon provides a biological basis or
formally described and mechanistically defined in the
mean for errorless learning, memory rehabilitation, or
1940s and 1950s (reviewed by Nosyreva and Huber, 2005).
storing an engram. Engram is a retrievable memory trace
In the absence of action potential, animal species would
or form, in which the brain transforms new memories.
respond like plants to external stimuli, for instance,
Long-term synaptic changes are not only highly input
slowly moving away or bending toward predators or nutri-
specific but also synapse specific or stimulate only those
ents on a time scale of hours or days. Action potential is
synaptic connections that have been activated or tagged
emitted (fired) by a neuron and is called an impulse or
by previous experience or signal (without affecting neigh-
spike train. Dendritic spines of any given neuron prin-
boring synapses). LTP results in the expression of genes,
cipally receive tens, hundreds, or thousands of discrete
synthesis of proteins, and recruitment of new receptors or
excitatory and inhibitory stimuli, which are gathered at
even synapses.
the soma. When an activation threshold is exceeded, the
neuron instigates a neural spike that is transported away
from the soma down the axon, resulting in the release of
Long-term depression the neurotransmitters at the axonal terminals synapses
and directed for intracellular transport (dendrite to soma
As a result of LTP, when synaptic connectivity reaches to axon to synapse).
the maximum level of efficacy and makes it difficult to
encode new information, a complementary process of LTD
selectively weakens such sets of synapses to maintain the Neuronal depolarization
synaptic strength. The low threshold of synaptic stimula-
tion instead can also stimulate NMDAR to produce LTD A stimulus received by the dendrites drives the inside
(Nosyreva and Huber, 2005). For LTD, the maintenance resting potential of the cells from -70  mV to -55  mV by

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allowing Na+ influx. Usually, the interior of the neuron
is 70  mV less than the outside, with relatively more Na+
present outside and more K+ present inside the neuron.
This increases the inside potential of the cell membrane
up to ∼+30 mV to result in neuronal depolarization.
Neuronal hyperpolarization
The closing of Na+ channels results in the opening of K+
channels. The system becomes neutral and impedes the
initiation of action potential if both channels (Na+ and
K+) open simultaneously. The depolarization has time to
be completed because the K+ channels open very slowly.
With the K+ channels open, the membrane gets back to its
resting potential by the process of repolarization. When
repolarization overshoots, hyperpolarization results and
resting membrane potential exceeds to around -90 mV.
Consequently, the threshold for receiving another stimu-
lus is raised during this time, or hyperpolarization pre-
vents the neuron from receiving any new stimulus and
assures that the signal is unidirectional. After hyperpolar-
ization, the membrane eventually establishes its resting
potential of -70 mV via Na+/K+ pump.
Activated PKA and PKC
Action potentials result in the activation of presynaptic
cyclic AMP (cAMP)-dependent kinases (protein kinase
A [PKA] and protein kinase C [PKC]). Activated PKA and
PKC that detect elevated levels of Ca2+ serve several func-
tions in synaptic plasticity with independent but over-
lapping spheres of action. Activated PKA and PKC entail
the covalent modification of a majority of proteins such
as the phosphorylation of two major (voltage-dependent
and voltage-independent) K+ channels (Baxter and Byrne,
2013) (Figure 2C).
Presynaptic glutamate release
When sensory neuron fires a subsequent action potential,
activated PKA and PKC enhance the release of presynap-
tic glutamate (that plays a central role, in assisting the
early phase of LTP) via the following two mechanisms
(Figure 2C):
–– The spike broadening-dependent mechanism: PKA
and PKC reduce specific K+ currents by phosphoryl-
ating K+ channels. It allows Ca2+ influx into the pre-
synaptic neuron via the extended span of an action
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Z. Amtul and A. Rahman: Synaptic plasticity and memory      259
potential (neuronal spike broadening) with an asso-
ciated elevation in excitability. This is manifested by
lowering the threshold potential, and it illustrates the
easiness of successive impulse generation process
by a neuron (Byrne and Kandel, 1996). The resultant
increased Ca2+ influx contributes to the enhanced
release of neurotransmitters.
–– The spike broadening–independent mechanism: This
mechanism acts directly on the exocytosis and mobi-
lization of presynaptic neurotransmitters containing
vesicles (Braha et al., 1990).
A transsynaptic postsynaptic pathway involves an EphB
receptor–ephrinB (type of adhesion protein) ligand inter-
action, which is activated by amplification in intracellular
Ca2+ within the postsynaptic neurons. For the mainte-
nance of an ongoing synaptic dialogue and its homeostasis
(Kleschevnikov and Routtenberg, 2001), this retrospective
signaling activates PKA. PKA activation further stimulates
neurotransmitter release (as shown from the mossy fibers)
(Contractor et al., 2002).
Modulatory neurotransmitters (dopamine, serotonin,
noradrenaline, and acetylcholine) act on their respective
receptors to activate cAMP-dependent signaling. This
serves as physiological effector of various brain states that
modulate the longevity of memory and synaptic plastic-
ity (such as reward, arousal, punishment and attention;
reviewed by Bliss and Cooke, 2011).
Postsynaptic depolarization
The strong depolarization of postsynaptic membrane
allows the repulsion of magnesium (Mg2+) ions, which
block the NMDAR ion pore (Nowak et  al., 1984) at near-
resting membrane potentials.
Glutamate binding to postsynaptic receptors
After release, glutamate binding to postsynaptic NMDAR
(known as depolarization) opens postsynaptic internal
reservoirs, including voltage- and ligand-gated cations
or Ca2+ channels, to allow Ca2+ influx to dendritic spines
(Lisman and Hell, 2008), shafts, and neuronal soma.
Ca2+ influx
Ca2+ influx triggers an intricate set of oscillatory and tran-
sitory signaling events, as follows:
260      Z. Amtul and A. Rahman: Synaptic plasticity and memory
–– In actin polymerization: Ca2+ can interact with the
actin polymerization cytoskeletons to remodel the
membrane blebbing or structural synaptic plastic-
ity of the synaptic bouton. This paves the way for
dendritic or axonal process outgrowth (reviewed by
Oertner and Matus, 2005).
–– In activating kinases: Within dendritic spines, the ini-
tial inflow of Ca2+ activates at least three key protein
kinases in the postsynaptic neural cell either directly
or indirectly. These are Ca2+/calmodulin-dependent
broad specificity Ser/Thr protein kinase II (CaMKII)
(Hudmon and Schulman, 2002), PKC (Nishizuka,
1992)/PKA (Lau et al., 2009), and the tyrosine kinase
Fyn (Grant et al., 1992).
CaMKII
CaMKII is considered a memory device, triggered by
synaptic Ca2+ and is highly enriched in the postsynaptic
region. CaMKII is required to transform or interpret the
diversity of Ca2+ signals into a more stable and perdur-
able message and to activate the cascade of intracellular
events that contribute in synaptic plasticity stabilization
(Lisman and McIntyre, 2001). CaMKII phosphorylates
various postsynaptic intraneuronal protein substrates,
such as PSD-95 (Yoshimura et al., 2000), F-actin (Allison
et al., 2000), densin-180 (Walikonis et al., 2001), and par-
ticularly NMDAR and AMPAR (Lee et  al., 2003). These
substrates are implicated in LTP expression via a likely
as-yet-unknown mechanism to encode, store, process
memory, and regulate synaptic plasticity (Figure 2E).
–– In translating Ca2+ signals: CaMKII keeps track of syn-
aptic events and retains a record of past Ca2+ influx
activity in terms of activated phosphorylation states.
CaMKII is even capable of interpreting or decoding
messages carried in the amplitude and duration of
individual Ca2+ spikes into different forms of long-
lasting Ca2+-independent activity (Raveendran et al.,
2009).
–– In microtubules: Microtubules are the candidate
sites for CaMKII phosphorylation-encoded molecu-
lar memory. By facilitating cellular cargo transport,
microtubules efficiently maintain neuronal archi-
tecture. A reorientation of this network is needed for
memory formation.
–– In potentiating LTP expression: CaMKII regulates its
activity via an intrinsic feedback mechanism such as
PKC. The catalytic subunit of CaMKII phosphorylates
the pseudosubstrate via protein kinase autophospho-
rylation to prevent the inhibition of phosphotransferase
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activity and to maintain kinase activation state. This
shows a critical means to continue signaling and has
a great significance for the consolidation of long-term
synaptic plasticity. In fact, at least 3 days after learning,
PKC can remain functional to parallel the length of acti-
vation observed after LTP (Lovinger et al., 1985).
CREB-1 activation
Work on Aplysia californica that has very few (approxi-
mately 20,000) neurons (Martin et al., 1997) and Drosoph-
ila (Drain et  al., 1991) demonstrated that with repetitive
training or persistent activation, synaptic PKA is trans-
ported to the nucleus to activate the transcription factor
cAMP response element binding protein 1 (CREB-1). CREB-1
then stimulates the formation of new synaptic connec-
tions by acting on downstream genes and activating the
protein synthesis. This eventually results in long-lasting,
much more robust changes in the strength of synapses.
Hippocampal CREB activation is absent in memory-
impaired rats with fornix lesions (Taubenfeld et al., 2001).
Immediate early genes
There are estimated to be tens to hundreds of immediate
early genes (IEGs). The IEGs reflect the earliest genomic
response to stimulation. In response to a particular
intense stimulus, the activity-dependent increase in the
synthesis of IEG products either represents the replenish-
ment signals from the accelerated activation of protein
turnover or forms new synapses. The translocation of
transcription factors that are present at the synapses
results in protein synthesis for replenishment (Freuden-
thal et al., 2004). Several IEGs have been identified, such
as the so-called effector IEGs (Narp, Arc, Cox-2, Rheb, and
Homer; Lanahan and Worley, 1998) that support effects
such as plastic changes by acting directly on cells and
factors that are transcription regulators of other genes
(c-jun, c-fos, Egr-3, and zif268). One important example
of IEG induction occurs when an altered light-dark cycle
stimulates animals to reset their endogenous circadian
rhythms (Takeuchi et al., 1993).
Targeting of newly synthesized proteins
The proteolytic susceptibility of newly synthesized indi-
vidual proteins, the homeostatic regulation of their levels
(calculated by their half-life), and the concentration

gradients guide their transport. These proteins are trans-
ported to the subcellular compartment, to the synaptic
nodes, and to axonal and dendritic processes that are
recently activated (by a process that is not well under-
stood), making the modification not only specific but
also permanent. This can affect the sensitivity, shape,
and therefore size of the pertinent synapses permanently.
These stabilized synapses form the network that becomes
the part of the brain’s long-lasting memory.
Synaptic tagging
Frey and Morris (1998) introduced the concept of synaptic
tagging. There are several theories of synaptic tagging. For
instance, one theory proposes that a molecular tag placed
at recently potentiated synapses ensures that the newly
translated relevant effector proteins are captured only
by synapses undergoing change and expressing the tag
(Redondo and Morris, 2011) not their neighbors. Another
theory states that a molecular tag triggers local protein
synthesis from newly transcribed or existing ribosomal
mRNAs found in the dendrites. Local translation would
radically decrease the quantity of protein molecules
needed to contribute to consolidate synaptic potentiation
or depression (Sutton and Schuman, 2006). The molecu-
lar tags are not identified yet.
Posttranslational modifications
It is also believed that the construction of fresh memo-
ries instead relies on activity-dependent synaptic PTMs
(reviewed by Routtenberg and Rekart, 2005). Although it
is not possible to describe all the PTMs that have an effect
on synaptic plasticity, a greater description would consist
of the following:
–– Phosphorylation: Protein phosphorylation has been
implicated in different forms of neural plasticity such
as neurite outgrowth, hippocampal LTP, and neu-
rotransmitter release (reviewed by Pasinelli et  al.,
1995).
–– Fatty acylation: The S-acylation of 16-carbon long
saturated fatty acid palmitate via a labile and revers-
ible thioester linkage to cysteine residues of neuronal
proteins (including secreted signaling molecules,
synaptic scaffolding proteins and neurotransmitter
receptors) is referred as palmitoylation. Likewise,
the posttranslational binding of prenyl moieties to
carboxy terminal of cysteine residue is called isopre-
nylation. The cotranslational binding of myristic acid
to the amino-terminal of glycine-containing motifs is
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Z. Amtul and A. Rahman: Synaptic plasticity and memory      261
called myristoylation. Palmitoylation greatly alters
the sorting and function of protein by affecting their
hydrophobicity (reviewed by el-Husseini and Bredt,
2002). Palmitoylation controls neurite outgrowth,
axon pathfinding, and neuronal differentiation and
regulates neurotransmitter release, membrane asso-
ciation, and receptor-clustering function of various
proteins in both presynaptic and postsynaptic nerve
terminals (reviewed by el-Husseini and Bredt, 2002).
Notably, palmitoylated PSD-95 seems to have an
important role in specifying synaptogenesis. In addi-
tion, the binding of other fatty acids, such as oleate,
arachidonate, and stearate, has also been described
(reviewed by el-Husseini and Bredt, 2002).
–– Glycosylation: The glucosamine, fucose, and N-acetyl-
neuraminic acid sugar moieties are attached to the
glycoproteins via glycosylation soon after they are
synthesized (Rose, 1995).
–– Acetylation: The acetylation of lysine residues on
histones by histone acetyltransferases is an obliga-
tory component of transcription (Swank and Sweatt,
2001).
–– Chelation: Electron-rich (Lewis base) moieties of
various polyanionic biomolecules cooperatively che-
late anionic coordination groups or binding pockets
with individual elemental cations confined to spe-
cific chelating nodes of the nECM. Trace monovalent
metal cations form short-lived monovalent metal
complexes [nECM/M+1]. Such metal complexes typi-
cally include water to form tetrahedral complexes
with coordination radii in the range of 0.2–0.3  nm
(2.2–3.3 Å) (reviewed by Marx and Gilon, 2013). For
long-term storage of cognitive information (Smirnov
et al., 2011), these monovalent metal complexes can
be stabilized as polyvalent metal complexes [nECM/
M+2/3/4/5]. The binding of Zn2+ to the transmembrane
protein tenascin (a component of the nECM) alters the
local lattice geometry of the haptide epitope of tenas-
cin. As a result, this conformational change perturbs
the polarizability, elasticity and resistivity of the neu-
ronal membrane, which membrane-embedded piezo-
electric or iontophoretic actuators recognize as an
encoding event. Knockout mice deficient in tenascin
exhibit defective memory (Kawakami and Matsumoto,
2011).
Reversible modifications of genomic DNA
The development of the neural circuitry in the brain
can be perceived as reversible modifications of genomic
262      Z. Amtul and A. Rahman: Synaptic plasticity and memory
DNA or epigenesis when many diverse components come
together at the right place and time. Only recently, it has
been shown that memory storage and other brain func-
tions involve epigenesis without changing the sequence
of underlying DNA. Epigenetic processes underlie cellu-
lar processes and molecular cascades crucial for memory
by influencing learning-associated transcriptional
changes.
Queen and worker honey bees
The role of epigenetic regulations in synaptic plasticity
is illustrated by the differences in the behavior of worker
and queen honey bees. Despite having identical genetic
makeup, worker and queen honey bees do not have identi-
cal behavior, including reproductive capacities, morphol-
ogies, and synaptic connections, which are found less in
the brains of queen bees. The reason for these striking dif-
ferences is their diet: worker bees are given royal jelly just
in the initial 3 days of their larval period, whereas queen
bees are fed with royal jelly throughout their lives. Inter-
estingly, reducing the levels of DNA methyltransferase
mimics the effects of royal jelly (Kucharski et  al., 2008).
Therefore, royal jelly in addition to controlling the epige-
netic development of canalization also keeps queen bees
from performing nonreproductive cognitively challenging
tasks. The reason to the behavioral plasticity of adult bee
must be altered synaptogenesis, as there is no noticeable
neurogenesis in the worker bee brain.
Potentiating LTP expression
To maintain prototypical Hebbian LTP and LTD, persis-
tent molecular modifications of individual synapses are
carried out via a number of mechanisms, such as the
following:
1. Via lack of dendritic mRNA: Little or no dendritic
mRNA is found for three postsynaptic proteins critical
for memory and neural plasticity (Kuhl and Skehel,
1998), that is, glutamate receptors, atypical isoform of
the Ca2+-dependent PKC (PKCγ), or neurogranin.
2. Via PKMζ: Plasticity-induced changes in postsynaptic
receptor trafficking involve insertion (increasing the
number) and removal of the AMPARs at the synaptic
membrane of glutamatergic synapses by the atypical
PKC, that is, PKMζ, for long periods. PKMζ is missing
a regulatory domain that is needed to put a brake on
its activity when elevated Ca2+ dissipates (Malenka
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and Bear, 2004) (Figure 2F). As a result, PKMζ main-
tains LTP expression for its lifetime at least possibly
by continual expression and autoregulation, which is
not yet completely known. Such neural plasticity pro-
duces long-term changes in the postsynaptic AMPAR
number and the AMPAR/NMDAR ratio. Concentra-
tions of NMDAR remain comparatively stable at these
synapses that participate in the maintenance of long-
lasting synaptic LTP (Bliss and Lomo, 1973).
3. Via CaMKII: CaMKII also participates in the long-
lasting LTP of synaptic transmission because it can
remain autonomously active by autophosphorylation
for longer period in the absence of elevated Ca2+. This
enables CaMKII to act as a molecular tag to permit
the staffing of newly formed proteins at recently acti-
vated synapses as a maintenance mechanism for LTP
(Redondo and Morris, 2011).
4. Via rehearsing and updating PTMs: Previously acti-
vated memories, including past events, are preserved
by updating and rehearsing the status of protein
PTMs via endogenous network activity (Ikegaya et al.,
2004).
5. Via multiple memory networks: One memory (even
for elementary procedures) is distributed among
multiple pathways and represented by different net-
works. A set of multiple re-entrant pathways that
are not indistinguishable maintain one memory.
These neural circuits are sufficiently analogous to
protect from memory loss even when majority of the
pathways are lost. Thus, no single consolidated net-
work is exclusively critical to a particular memory
(­Handelmann and Olton, 1981).
6. Via brain-derived neurotrophic factor (BDNF): CREB
and mitogen-activated protein kinase (MAPK) signal-
ing results in the synthesis of BDNF. BDNF is a neuro-
trophic factor; its role in neural plasticity is complex
and multimodal. It is coreleased with presynaptic glu-
tamate to take part in the early LTP and LTD phases.
As pro-BDNF, BDNF binds to two postsynaptic recep-
tors that result in the promotion of subsequent LTD
induction: the P75 receptor, which leads to the modifi-
cation of NMDAR subunit composition when activated
(Woo et  al., 2005), and the tyrosine kinase B (TrkB)
(Figurov et al., 1996) (Figure 2G). BDNF also initiates
structural changes, critical for memory consolidation
at tagged synapses, such as dendritic growth, axon
path finding, neuronal migration, and formation and
preservation of the synaptic contact, for example, the
sprouting of hippocampal mossy fiber (Epsztein et al.,
2005) (Figure 2H).
 Z. Amtul and A. Rahman: Synaptic plasticity and memory      263

Offspring of undernourished mothers associated with synaptic development, maintenance, and

In addition to decreased synaptogenesis, neuronal sur-
vival, synaptic plasticity, reduced object, and spatial rec-
ognition, offspring of undernourished mothers also show
decreased hippocampal BDNF mRNA and protein levels
(Fischer et al., 2007).
Structural synaptic changes with
plasticity. Although majority of new spines have short life
span, training-specific spines are created and last longer
after the task, and around 0.04% are estimated to last
until the end of the mouse’s life (Ziv and Ahissar, 2009).
At the morphological level, LTD is associated with the
shrinkage or loss of spines and removal of postsynaptic
AMPARs, whereas LTP can generally induce the enlarge-
ment of dendritic spines (Zhou et al., 2004). In addition,
dendritic spines are greatly motile during development.

learning Stimulation of either AMPARs or NMDARs inhibits this

motility (Fischer et  al., 2000). The dendritic spine mor-
phology is also regulated by astrocytes involving bidirec-
Structural reorganization of synapses is one of the ways to
tional ephrin/EphA signaling through a contact-mediated
preserve synaptic plasticity. It is not clear yet up to what
mechanism (Carmona et al., 2009).
degree structural synaptic alterations (accompanied by
the long-term memory storage) occur in an adult brain.
For instance, during sensitization and habituation, the
Presynaptic terminals
gill-withdrawal reflex learning results in striking structural
changes along with abrupt and short-term alterations in the
The sensory neurons from the habituated Aplysia (behav-
function of synapses. These changes occur in the synaptic
ioral memory) retract some of their presynaptic terminals
strength not only between sensory and motor neuronal
to weakly associate with motor and interneurons com-
connections but also between the sensory and interneu-
pared with the sensory neurons in nonhabituated Aplysia
ronal connections (Frost and Kandel, 1995). The studies
(Bailey and Chen, 1988a). By contrast, the number of
illustrated that different learning forms at different stages
presynaptic terminals of the sensory neurons, after long-
of memory can alter a single synaptic connection in oppo-
term sensitization, increases more than two-fold (Bailey
site ways for minutes to weeks. Results show that even very
and Chen, 1988a). Sensory neurons are not exclusively
basic forms of learning and memory are accompanied by
affected by this learning-induced synaptic growth. An
obvious alterations in the structure of both pre- and post-
augmentation in the size and number of active zones on
synaptic neurons and the number of functional synapses
each side of the synapse has also been reported.
that decisively participate in behavioral modification.

Postsynaptic dendrites
Synapses
The dendrites of the postsynaptic motor neurons have been
Alterations in the morphology of preexisting synapses
shown to be remodeled and grown to aid in the receipt of
constitute such structural changes. It also includes the
ancillary sensory input (Bailey and Chen, 1988b).
formation and persistence of new synaptic connections
(as observed by the appearance of augmented distribu-
tion and density of new dendritic spines) as well as the
Axons
strengthening, weakening, and elimination of existing or
old synapses. In this regard, the astrocytic thrombospon-
Neuronal migration and axonal guidance also constitute
din family of extracellular matrix proteins has been iden-
synaptic structural changes. The structural remodeling of
tified as the synaptogenic signal (Christopherson et  al.,
the synaptic bouton and actin cycling (Fitzsimonds and
2005). Glial cells have also been shown to play a key role
Poo, 1998) is also observed at active synapses.
in synapse formation (Bolton and Eroglu, 2009).

Dendritic spines Receptors

Under normal physiological conditions, alterations in the Structural changes may be driven by initial activation of one
number and morphology of dendritic spines are frequently or several neurotransmitter receptors all the way through the

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264      Z. Amtul and A. Rahman: Synaptic plasticity and memory
memory consolidation process. The number and/or loca-
tion of postsynaptic receptors, ion channels, and synaptic
scaling of the AMPARs (to stabilize firing rates up or down)
can also be modified over both short and long periods.
Memory loss
The breakdown of the neural networks/arrays at any criti-
cal point is manifested as circuit or storage failure, includ-
ing memory loss, as the cognitive information encoded
therein also decays.
Synapse
Synaptic abnormalities are now identified as primary for
various neurological and mental disorders, such as those
related to neurodegeneration, trauma, addiction, and
aberrant development.
Autism
At present, the etiology of autism is poorly understood.
Deficits in synaptic refinement and synaptogenesis are
being proposed to be a primary basis of autism. Mutations
in genes that generally direct the synaptic maturation
pattern of specific subpopulations of neurons are shown
to segregate with the pathological phenotype (Polleux
and Lauder, 2004; Gatto and Broadie, 2010).
Alzheimer’s disease
Patients with this progressive neurodegenerative syn-
drome of the association and limbic cortices have well-
preserved motor and sensory functions and cannot
store fresh memories anylonger, initially of minor type
and then significant details of life. Many morphological
and biochemical measures indicate that Alzheimer’s
disease (AD) is characterized by an attack on syn-
apses, at least initially, in addition to the neurotrans-
mitter alterations (Terry et  al., 1991; Sze et  al., 1997).
Increasing evidences imply that subtle alterations in
LTP and/or basal synaptic transmission of hippocam-
pal synaptic efficacy precede the massive degeneration
of neurons observed later in AD. Diffusible oligomeric
assemblies of the β-amyloid (Aβ) protein cause the syn-
aptic dysfunction.
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Down syndrome
A great majority of studies have shown that uncontrolled
levels of inhibition in the medial temporal lobe of Ts65Dn
mice caused a failure of long-term synaptic plasticity in
their hippocampus, resulting in cognitive impairment
(Kleschevnikov et  al., 2004; Fernandez et  al., 2007).
In addition to the increased immunoreactivity for syn-
aptic proteins at cortical and hippocampal inhibitory
synapses, these defects in synaptic plasticity are also
associated with striking alterations in the structure of
synapses. Similarly, active zones at inhibitory synapses
are selectively enlarged (Belichenko et  al., 2009; Porez-
Cremades et al., 2010).
Neuronal depolarization
Interestingly, through epigenetic dysregulation, neu-
ronal depolarization can result in the alternative splicing
of certain genes (Schor et al., 2009). Access to memories
lost due to severe neural degeneration can be reinstated
by sodium butyrate treatment, which can also increase
synapse numbers and induce dendritic sprouting (Fischer
et al., 2007).
Spinal muscular atrophy, Rett syndrome, and schizo-
phrenia are linked to alternative splicing (Licatalosi and
Darnell, 2006).
Synaptic proteins
Recently, in screens for genetic mutations associated with
psychiatric and neurodevelopmental disorders, a big
milestone has been achieved in discovering the primary
role of synaptic proteins in many brain diseases (Bayes
et al., 2011). There is a likelihood that some subsets of spe-
cific brain circuits/synapses are more susceptible to a par-
ticular pathological condition than others, as a majority of
synaptic proteins associated with different diseases have
regionally diverse distributions. This raises the intriguing
possibility that by unique molecular signatures of atypi-
cal synaptic protein expression patterns, we may one day
recognize a particular neurological and mental disorder
(Bayes et al., 2011).
In AD, alterations in the levels of synaptophysin,
a presynaptic vesicle protein in the hippocampal and
association cortices, has been linked with the extent of
memory dysfunction in AD patients (Terry et al., 1991; Sze
et al., 1997).

Metals
As with many proteins, the perturbations in metal ion
homeostasis within the brain may also result in cerebral
damage (reviewed by Duce and Bush, 2010). The altera-
tions in the optimum concentrations of elemental metals
such as metal toxicity or deficiency are manifested as
clinically observable changes in various behaviors (con-
fusion, disorientation, poor learning, and personality
changes) as well as dysfunctional memory or memory loss
(Llinas, 1988; Jefferys, 1995; Lieleg et  al., 2009; Smirnov
et al., 2011).
AD and Wilson’s disease
Trace metals are related to diseases, such as aluminum
and zinc in AD, copper in Wilson’s disease, and sulfhydryl-
reactive metals in autism. Similarly, Li salts and zinc salts
are also recommended for treatment (Johnson, 1981; Kern
et al., 2007; Curtis et al., 2010; Priya and Geetha, 2011).
Chelation drugs
The memory-enhancing effects of zinc salts or chelation
drugs suggest that the optimal levels of free (diffusible)
cerebral metal ions are necessary for the maintenance
of memory. Aspirin, desferrioxamine, EDTA, and penicil-
lamine are some of the chelation drugs that have been
shown to have an effect on memory process. Similarly,
it is reported that zinc binding by drug interrupts hip-
pocampal-dependent spatial working memory. The use of
iron chelators has been shown to treat age-related cogni-
tive impairment, and aspirin is used for greater prospec-
tive memory dysfunction on select measures (Priya and
Geetha, 2011).
Conclusion: synaptic plasticity
and missing links
As outlined in the previous sections, a significant amount
of work has been published on synaptic plasticity, which
illustrates the molecular and structural outlook of the
learning and memory mechanisms. However, this infor-
mation about memory encoding is inadequate and still
argues for different persistent edifying mechanisms
at the level of synapse. As we have reviewed recently
(Amtul and Rahman, 2014), the molecular mechanisms
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Z. Amtul and A. Rahman: Synaptic plasticity and memory      265
and cellular mediators of the hydrogen bonding pattern
may uncover this interplay between individual neurons.
In that review, we have proposed the hydrogen bonding
pattern as a compensatory form of change in synaptic
strength and the molecular mechanism that counteracts
alterations due to LTP and LTD to assist in stabilizing the
activity of neuronal or synaptic network. We further pro-
posed developing the theories and experiments that may
elucidate the inter- and intramolecular hydrogen bonding
patterns in detail.
Acknowledgments: The authors disclose the receipt of
financial support from the Higher Education Commission,
Pakistan, for the research, authorship, and/or publication
of this article.
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