Synaptic plasticity

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Week 10

Property Chapter 8

Short-term synaptic plasticity

Chemist synapses - capable of undergoing plastic changes → either strengthen/

weaken synaptic transmission.

The short-term forms of plasticity - lasting for few mins → observed during repeated
act. of any chemical synapse.

Synaptic facilitation - rapid incr. in synaptic strength → occurs when 2~more

actions - invade the presynaptic terminal w/in few millisec of ea. other.

→ the result of prolonged elevation of presynaptic Ca levels ~ folowing synaptic act.

Action potential arrive close together - Ca builds up in the terminal → allows more
neurotransmitter to be released by subsequent pre-synaptic action potential.

Ca2+ binding protein - found on plasma membrane ~ related to the

synaptotagmins.

~ present on synaptic vesicles → serve as Ca2+ sensors for triggering

neurotransmitter release.

Synaptic depression - causes neurotransmitter release → decline during

sustained synaptic act.
bc. of synaptic depression - comes from observations → depression depends on
the neurotransmitter amount has been released.
→ The total amount of depression - proportional to the amount of transmitter
released from presynaptic terminal.

Synaptic plasticity 1
 ~ depression caused by progressive depletion of pool synaptic vesicles - avail. for
release.
→ rates of release - high, depletion rapidly and cause a lot of depression, vice
versa.

Depression causes the strength of transmission to decline ~ until this pool is

replenished by mobilisation of vesicles from reverse pool.
→ more depression observed after the size of reverse pool - reduced by impairing
synapsin ~ protein maintains vesicles in the reverse pool.

Synaptic potentiation & augmentation - elicited by repeated synaptic act. →

serve to incr. the amount of transmitter released from presynaptic terminals.
⇒ both enhance the ability of incoming Ca2+ - trigger fusion of synaptic vesicles w.
the plasma membrane.

Augmentation - rises and falls over a few secs.

→ Ca2+ enhancing the actions of presynaptics SNARE-regulatory protein
munc-13.

Potentiation - acts over timescale of tens of secs to mins → greatly outlast the
tetanic stimulus that induces it (post-tetanic potentiation PTP)

→ Ca2+ activates presynaptic protein kinases - go on to phosphorylate

substrates → regulate transmitter release.

During repetitive synaptic act, the various forms of short-term plasticity → interact to
cause synaptic transmission to change in complex ways.

repeated act. - causes an accumulation of Ca2+ in the presynaptic terminal →

allows facilitation ~ augmentation to enhance synaptic transmission.

⇒ ensuing depletion of synaptic vesicles - causes depression to dominate &

weaken the synapse.

These forms of short-term synaptic plasticity - cause transmission at all chem.

synapses → change dynamically ~ consequence of recent history of synaptic act.

Synaptic plasticity 2
 Long-term synaptic plasticity & behavioural modification in Aplysia

Facilitation, depression, augmentation, potentiation → modify synaptic transmission

over timescales of few minutes/less.

⇒ responsible for many short-lived changes in brain circuitry - cannot provide the basis
for changes in brain function ~ persist for weeks, months, years.

Many synapses - exhibits long-lasting forms of synaptic plasticity → plausible

substrates for more permanent changes in brain region.
→ may be cellular correlates of learning and memory.

Plasticity - fundamental that its essential cellular & molecular underpinnings → be

conserved in the nervous systems of very diff. organisms.

⇒ success in identifying several forms of long-term synaptic plasticity ~ demonstrate

forms of synaptic plasticity underlie simp. forms of learning.

These attributes make it practical to monitor the electrical act. of spec., identifiable
nerve cells

→ define the synaptic circuits invol. in mediating the limited behavioural repertoire
of Aplysia.

Aplysia - exhibit several elementary forms of behavioural plasticity.

Habituation - process causes the animal to become less responsive to repeated

occurences of stimulus.

Sensitization - process that allows an animal to generalise an aversive response →

elicited by noxious stimulus ~ to non-noxious stimuli.

⇒ Aplysia that have habituated to siphon touching, sensitization of gill withdrawal is

elicited by pairing a strong electrical stimulus to the animal’s tail with another light touch
to the siphon.

Even after a single stimulus to tail → gill withdrawal reflex - remains enhanced for at
least an hour.

(short-term memory)

Synaptic plasticity 3
 The small no. of neurons in Aplysia nervous system → poss. to define the synaptic
circuits invol. in gill withdrawal ~ monitor the act of indv. neurons in these circuits.
→ only few diff. types of neurons can account for gill withdrawal + its plasticity
during habituation + sensitization.

Critical neurons incl. mechanosensory neurons - innervate the siphon ~ motor

neurons - innervate muscles in the gill ~ interneurons that receive inputs from
variety of sensory neurons.

Touching the siphon - activates the mechanosensory neurons → forms excitatory

synapses - release glutamate onto both the interneurons + motor neurons.

→ incr. the prob. ~ both these postsynaptic targets will produce action potentials.

The interneurons → form excitatory synapses on motor neurons ~ incr. the

likelihood of motor neurons firing action potentials in response to mechanical
stimulation of siphon.

The motor neurons - activated by summed synaptic excitation of sensory neurons +

interneurons
→ release acetylcholine - excites the muscle cells of the gill , producing gill
withdrawals.

Both habituation + sensitization → appear to arise from plastic changes in

synaptic transmission in this circuit.

Synaptic depression - thought to be responsible for the decreasing ability of siphon

stimuli → evoke gill contraction during habituation.

sensitization - modifies the function of this circuit by recruiting additional

neurons.

→ sensory neurons excite modulatory interneurons - release serotonin onto the

presynaptic terminals of the sensory neurons of siphon.

serotonin - enhances transmitter release from siphon sensory neuron

terminals → leads to incr. synaptic excitation of motor neurons.

→ binds to G-protein-coupled receptors on the presynaptic terminals of

siphon sensory neurons (1) ~ stimulates production of 2nd messenger -

Synaptic plasticity 4
 cAMP (2) ~ binds to the regulatory subunits of protein kinase A (3) ~
liberating catalytic of PKA → phosphorylate several proteins incl. K+ (4).

~ the net effect of action PKA reduce the prob. that K+ channels open during
presynaptic action potential → opening more presynaptic Ca2+ channels (5)
~ enhanced the influx of Ca2+ into the presynaptic terminals - incr. the
amount of transmitter released onto motor neurons during sensory neuron
action potential (6).

The short-term sensitization apparent → recruitment of additional circuit

elements → the modulatory interneurons - strengthen synaptic transmission in the
gill withdrawal circuit.

serotonin-induced enhancement of glutamate release ~ plays role in both short-

term & long-term sensitization.

invol. transient changes in synaptic strengths → require gene expression/

protein synthesis.

the circuitry - affected for several weeks ~ prolonged duration of this plasticity
→ attributed to changes in gene expression + protein synthesis.

Synaptic plasticity 5
 Role of CREB

bind to cAMP response elements

(CREs) in nuclear DNA → incr.
the transcription of downstream
genes.

stimulates the synthesis of

enzyme (ubiquitin hydrolase) →
degrades the regulatory PKA.

→ long-lasting incr. in the amount

of free catalytic PKA ~ making
PKA persistently active w.o the
need for serotonin.

activates another transcriptional

activator protein (CEBP) →
stimulates the transcription of
unknown genes ~ responsible for
addition of synaptic terminals

→ results in long-term incr. in no.

of synapses.

activates mRNAs - imp. for local

control of protein synthesis.

self-sustaining properties - allow

it to remain active indefinitely →
mediate permanent changes in
synaptic structure ~ generate
long-term sensitization.

Long-Term Potentiation at a Hippocampal Synapse

Long-term synaptic plasticity incl. LTP (long-lasting potentiation) & LTD (long-
lasting depression) → processes invol. long-lasting incr. / decr. in synaptic

Synaptic plasticity 6
 strength.
→ synaptic efficacy - occur at diff. synapses thru. brain ~ mediated by various
cellular & molecular mechanisms.

LTP

exhibits spec. prop. - make it an attractive mechanism for info. storage.

→ require strong act. in both presynaptic & postsynaptic neurons ~ w. a crucial

requirement for coincident act. of these neurons.

→ strengthen synaptic connections.

excitatory synapses in various brain regions (cortex, amygdala, cerebellum) +

some inhibitory synapses.

an input spec. - restricted to synapses have been activated → allows for

selective enhancement of particular sets of inputs ~ making it well-suited for
memory formation + selective info. storage.

Associativity - refers to phenomenon → one pathway weakly activated w.

another that strongly act. the same cell - BOTH undergo LTP.
⇒ results of the coincidence detection feature of LTP - spec. invol. the
pairing of weak synaptic act. w. the coincident generation of action potentials by
strong synapses.

resembles a cellular analog of associative learning ~ required for learning to

occur
eg. Associative learning - classical conditioning → learns to associate
things.

→ link one set of info. w. another.

⇒ provide plausible mechanism - produce lasting neural changes w/in the

hippocampus ~ brain regions associated w. certain types of memory.

Synaptic plasticity 7
 💡 Late 1960s when TJ & TB made sig. discoveries.

→ reveal the brief high-freq. electrical stimulation → enhance synaptic

transmission in the rabbit hippocampus ~ changes could persist for
hours/ longer.

LTP studies - adv. thru. studies of living hippocampus slides.

→ allows researchers to maintain relevant circuitry ~ studying
synaptic plasticity under controlled conditions.

Hippocampus

brain regions - been thru. studies in the context of long-term synaptic plasticity.

crucial role in certain types of memory formation & retrieval.

activated during specific of memory tasks

→ damage to this brain region results in inability to form certain types of new
memories.

can be sectioned to perserve its circuitry.

CA1 & CA3 - major components of hippocampus

Dendrites of pyramidal cells in CA1 form a thick band ‘stratum radiatum’

Schaffer collaterals - axons of pyramidal cells in CA3 provide synapses to

CA1 regions.

Electrical stimulation of Schaffer collateral - generates excitatory

postsynaptic potentials (EPSPs) in postsynaptic CA1 cells.

Low-freq. stimulation → not produce LTP → EPSPs remain constant.

→ high-freq. train of stimuli - applied to induces LTP → long-lasting incr. in

EPSP amp.

Synaptic plasticity 8
 Mechanism underlying long-term potentiation

Antagonists of NMDA-type glutamate receptor - found to prevent LTP during

high-freq. stimulation of Schaffer collaterals.

→ no effect on the synaptic response produced by low-freq. stimulation.

NMDA receptor- exhibits unique biophysical properties → understanding how LTP

selectively induced by high-freq. act.

permeable to Ca2+ ions/ blocked by Mg2+ ions at normal resting membrane

potential.

act as molecular coincidence detector:

opens to induce LTP ~ only when glutamate binds to receptor.

~ simul. postsynaptic cell - must be depolarised to relieve the Mg2+ block of

channel pore.

During high-frequency stimulation

summation of EPSPs leads to a prolonged depolarization, expelling Mg2+ from the
NMDA channel pore ~ allowing Ca2+ to enter the postsynaptic dendritic spines of CA1
neurons.
During low-frequency synaptic transmission
glutamate released by the presynaptic Schaffer collaterals binds to both NMDA-type
and AMPA-type glutamate receptors

Mg2+ blockade - prevents current flow thru. the NMDA receptors

→ making the excitatory postsynaptic potential (EPSP) mediated by AMPA receptor.

The requirement for strong coincident presynaptic + postsynaptic act →

induce LTP arises bc. presynaptic glutamate release - coincides w. postsynaptic
depolarisation
→ relieving the Mg2+ block.

Synaptic plasticity 9
 Associativity - achieved when weakly stimulated input - insufficient to depolarise the
postsynaptic cell → activate NMDA receptors

inputs strongly stimulated → provide the necessary associative depolarisation

to relieve the block.

Accumulation of postsynaptic Ca2+ due to Ca2+ influx thru. NMDA receptors →

LTP induction.

activation of NMDA → incr. postsynaptic Ca2+ levels ~ localised to dendritic

spines of indv. synapses.
→ blocking postsynaptic Ca2+ w. chelators - prevents LTP induction ~ elevating
Ca2+ levels - enhances synaptic transmission.

The expression of LTP - invol.

dynamic changes in AMPA at
postsynaptic membrane.
→ result from the insertion of AMPA
into postsynaptic membrane
mediated by synaptotagmin.

AMPA receptor - originate from

recycling endosome.

incr. in AMPA amplifies the

postsynaptic response to
glutamate

→ lead to strengthen
synaptic transmission -
persist as long as LTP is
maintained.

LTP modify ‘silent synapses’ -

lacked postsynaptic AMPA →
adding AMPA to produce
postsynaptic responses.

Synaptic plasticity 10
 CaMKII - central role in LTP
at Schaffer collateral
synapses → its activation
associated w. LTP induction.

inhibition/ genetic
deletion of CaMKII →
prevents LTP.

Both CaMKII & PKC -

phosphorylate downstream
targets incl. AMPA receptors

→ enhance the delivery of

extrasynaptic AMPA to
synapse.

Later phase of LTP - depends on

changes in gene expression +
synthesis of new proteins
→ suggest a transition from rapid
molecular processes ~ to long-lasting
structural changes.

initiated by protein kinase A

(PKA) - act. transcription factors
(CREB - stimulate expression of
other proteins).

blocking proteins synthesis w.

drugs → inhibits later phase BUT
not affect early phase.

Synaptic plasticity 11
 💡 Both forms of long-term synaptic plasticity - involved in longterm storage of
information ~ although the role of LTP in memory storage in the hippocampus
is not firmly established.

Mechanism underlying long-term depression

LTD depresses the excitatory postsynaptic potential (EPSP) for several hours -
specific to the activated synapses.

LTD - erase the increase in EPSP size due to prior LTP, vice versa.
→ suggests a reversible impact on synaptic efficiency - indicating a common
site of action for both LTP and LTD.

Both LTP & LTD - invol. the act. of NMDA + entry of Ca2+ into postsynaptic
cell.
→ Ca2+ signals w. postsynaptic cell - appears to determine whether LTP/LTD
occurs.
(small/ slow incr. - LTD ~ large/fast incr. - LTP)

Kinase contributes to LTP maintenance + expression.

LTD results from the act. of phosphatases → Ca2+ dependent phosphatases ~ not
affect LTP.

Late phase LTD - requires the synthesis of new proteins.

→ proteins - regulate synaptic transmission efficacy.

Cerebellar LTD - located in cerebellum → implicates for motor learning &

coordination.

synaptic inputs onto Purkinje cells - reduced in strength ~ contribute to motor

learning.

form of LTD - associative as occurring when 2 distinct excitatory inputs, climbing

fibers & parallel fibers activated simul.

Synaptic plasticity 12
 Glutamate released from parallel fiber terminals - act. 2 types of receptors
(AMPA + metabotropic receptors).

Glutamate binding to AMPA receptor - results in mild membrane depolarisation

~ binding to metabotropic receptor produces the 2nd messenger (IP3) & (DAG).

→ cause. an amplified rise in intracellular Ca2+ concentration by acting

together on IP3 receptors - lead to synergistic act. of PKC by Ca2+ and DAG.

Glutamate released by climbing fibers - act. AMPA receptors → strongly

depolarise the P cell membrane potential → initiates a 2nd signal transduction
pathway.

The main consequence of PKC -dependent phosphorylation → cause an

internalisation of AMPA via. clathrin-dependent endocytosis.

Loss of AMPA - decr. the response of the postsynaptic P cells ~ to glutamate

released from presynaptic terminals of parallel fibers.

The net effect - same in both case of LTD and cerebellar LTD →
internalisation of postsynaptic AMPA - mechanism decr. efficacy of both
hippocampal & cerebellar synaptic during LTD.

Synaptic plasticity 13
 Spike timing-dependent plasticity
1. Timing-Dependent Plasticity:
LTP and LTD are not only
influenced by the rate of
repetitive synaptic activity ~ but
also by the precise temporal
relationship between activity in
the pre- and postsynaptic cells.
2. Direction of Plasticity:
The direction of plasticity (LTP or
LTD) depends on whether
presynaptic or postsynaptic
Synaptic plasticity
1. Sensitivity to Timing:
The relationship between the
time interval between pre- and
postsynaptic activities and the
magnitude of synaptic change is
highly sensitive to timing.
No changes are observed when
the activities are separated by
100 milliseconds or longer.
2. Ca2+ Signaling in STDP:
14
 activity precedes the other at a The mechanisms of STDP are
given low frequency of synaptic not yet fully understood - involve
activity. timing-dependent differences in
postsynaptic Ca2+ signals.
3. Functional Implications of STDP:
Postsynaptic action potentials
STDP can encode information
can lead to Ca2+ influx through
about causality, such as whether
NMDA receptors → varies in
a postsynaptic action potential
magnitude depending on the
results from the activity of a
timing of pre- and postsynaptic
specific synapse → lead to
activities, resulting in LTP or LTD.
competition between synaptic
inputs, favoring stronger inputs. 3. Clinical Implications:
STDP has been found to play
The passage briefly mentions
roles in neural circuit function
that abnormal patterns of
incl. determining orientation
neuronal activity, as seen in
preference in the visual system.
conditions like epilepsy, can lead
4. Challenges in Understanding to abnormal changes in synaptic
Memory Encoding: connections. This highlights the
potential relevance of synaptic
The passage acknowledges that
plasticity in understanding
despite substantial advances in
neurological disorders.
understanding the cellular and
molecular bases of some forms
of plasticity - remains unclear
how selective changes in
synaptic strength → encode
memories or complex behavioral
modifications in the mammalian
brain.

Synaptic plasticity 15