SYNAPTIC PLASTICITY: modification of the synaptic efficacy

induced by the previous neural activity

Short-term synaptic plasticity (msec-min)

-> occurs at all synapses during repetitive activity (AP sequences at
physiological frequencies) and has key role in computations performed
by neural circuits

Long-term synaptic plasticity (hours-years)

-> it is induced by specific patterns of activity and has key role in
learning and memory

Nervous system plasticity: modification of behaviour

induced by previous experience (learning, memory, habits)
As a consequence of short-term synaptic plasticity, the effect
of an AP in a presynaptic neuron on the activity of the
postsynaptic neuron can greatly vary depending on the
previous sequence of presynaptic APs.
Nervous system plasticity: modification of behaviour
induced by previous experience (learning, memory, habits)

Learning: the process with which new information is acquired and

encoded by the nervous system (i.e. the process with which knowledge
of the world is acquired)
Memory: the process with which the acquired knowledge is stored and is at a
later time recalled

There are different types of memory, depending on its

duration and the type of information being stored
SYNAPTIC PLASTICITY: modification of the synaptic efficacy
induced by the previous neural activity

Many different mechanisms underlie synaptic plasticity

-Presynaptic mechanisms: modification of the quantity of

neurotransmitter which is released
Presynaptic mechanisms can be intrinsic or extrinsic (i.e. involve other neurons,
e.g. via axoaxonic synapses or release of neuromodulators)

-Postsynaptic mechanisms: modification of the postsynaptic

response to a given concentration of neurotransmitter

Different mechanisms can lead to:

-increased synaptic efficacy

-decreased synaptic efficacy

 Average PSP = npq
n = number of ready-releasable vesicles at the synapse (RRP: ready-
releasable pool);
n coincides with the number of primed vesicles at synapses where multivesicular
release can occur or with the number of active zones at synapses where only one
vesicle per active zone can be released

p= probability of release of a ready-releasable vesicle

p depends on:
- the local Ca2+ transient (which depends on the number and kinetics of CaV channels
at the active zone and their distance from the primed vesicle, the AP shape, the Ca2+
buffer and the Ca2+ extrusion mechanisms at the active zone)
- the affinity of the Ca2+ sensor

-q= quantal amplitude (PSP produced by release of one vesicle)

q depends on the number and affinity of postsynaptic receptors and the content of
neurotransmitter in a vesicle

n and p depend on (and may change during AP sequences as a consequence of )

presynaptic mechanisms

q depends on (and may change during AP sequences as a consequence of)

postsynaptic mechanisms (assuming constant content of neurotrasmitter in vesicle)
 SHORT-TERM synaptic plasticity

Different mechanisms characterized by different time scales of development and

decay of short-term plasticity can lead to
-increase of synaptic efficacy:

Facilitation (lasts hundreds of msec)

Potentiation (augmentation: 5-10 sec; Post-tetanic potentiation,
PTP: 30 sec-min)

Facilitation and potentiation are presynaptic mechanisms:

due to increase of the probability of release of ready-releasable vesicle (p) and/or of
the number of ready-releasable vesicles (n), resulting in increase of probability of
neurotransmitter release at the synapse (increase in quantal content np, i.e. the
average number of vesicles released by an AP)
 SHORT-TERM synaptic plasticity (STP)
Different mechanisms characterized by different time scales of development and
decay of short-term plasticity can lead to
-increase of synaptic efficacy dependent on previous activity:

Facilitation (lasts hundreds of msec)

Potentiation (augmentation: 5-10 sec; Post-tetanic potentiation,
PTP: 30 sec-min)

Facilitation and potentiation are presynaptic mechanisms:

-Decrease of synaptic efficacy dependent on previous activity:

Depression

Many different mechanisms of depression:

most presynaptic, some postsynaptic
 Facilitation
The facilitation can be observed with paired pulses (APs) separated by tens of ms,
in which the PSP elicited by the 2° AP can be up to 5 times that elicited by the 1° AP.
During brief sequences of APs the PSP can increase up to more than 10 times

It is characterized by rapid development and rapid decay

(hundreds of ms time scale).
 Potentiation
The potentiation can be observed after long trains of APs at relatively high frequency;
the increase in PSP develops more slowly during the train (1-15% increase per AP)
than in the facilitation and also decays more slowly, hence potentiation lasts much
longer than facilitation (augmentation: 5-10s; PTP: 30s- min).
At several synapses, there is facilitation during the first APs in the train followed by
augmentation and then PTP (but the latters are difficult to distinguish).
(teta (tetanic) stimulation
High-frequency

Presynaptic APs (mV)

PSPs (mV)
 In general at a given synapse, mechanisms leading to short-term increase of
synaptic efficacy (potentiation and/or facilitation) and to short-term decrease of
synaptic efficacy (depression) coexist. The observed short-term plasticity depends
on which mechanism prevails, and this depends on the details of the presynaptic
activity (AP frequency, neuromodulation) and on the specific synapse.

Facilitation + PTP
Presynaptic APs: + depression
at time 0: train of APs
at 10 Hz for 10 sec
preceded and followed
by control APs at 1 Hz

The time scale of

development of and
recovery from depression
is intermediate between
that of facilitation and PTP.

At certain synapses the

depression prevails during the
high-frequency AP train and the
potentiation is observed only
after the train and after
recovery from depression,
hence the name PTP
 Mechanisms underlying facilitation
(first hypothesized by Katz and Miledi , 1968)
The facilitation depends on the residual Ca2+

Residual Ca2+ from the

1st AP increases p
release at the 2nd AP by
increasing the local Ca2+
concentration at the
vesicular Ca-sensor
The duration of
facilitation depends on
the time necessary to
remove residual Ca2+

Evidence:
1. Linear relationship between facilitation and [Ca2+]in (measured with fluorescent dyes)
2. Exogenous buffers EGTA e BAPTA reduce the facilitation
 Mechanisms underlying facilitation

The facilitation depends on the residual Ca2+ (first hypothesized by Katz and Miledi , 1968)

Residual Ca2+ from the

1st AP increases
Prelease at the 2nd AP by
increasing the local Ca2+
concentration at the
vesicular Ca-sensor

Evidence:
1. Linear relationship between facilitation and [Ca2+]in (measured with fluorescent dyes)
2. Exogenous buffers EGTA e BAPTA reduce the facilitation

But:
increase of residual Ca2+ per AP (about 1 uM) is too small to explain the increase
in Prelease (cf up to 5 times facilitation of the EPSP at the 2° AP), assuming that
residual Ca2+ acts on the Ca-sensor for rapid release (synaptotagmin).

In fact, if [Ca]rest + [Ca]loc (100 nM +20 uM) is the [Ca] at the Ca-sensor that induces release in response
to the first AP, and [Ca]rest + [Ca]loc + [Ca]res (100 nM + 20 uM + 1 uM) is the [Ca] that induces release in
response to the 2° AP, considering the dependence of release on [Ca]4, one calculates a 20% increase of
release (much smaller than that observed up to >10 times).
 Mechanisms underlying facilitation

The facilitation depends on the residual Ca2+ (first hypothesized by Katz and Miledi , 1968)

Residual Ca2+ from the

1st AP increases
Prelease at the 2nd AP by
increasing the local Ca2+
concentration at the
vesicular Ca-sensor

Evidence:
1. Linear relationship between facilitation and [Ca2+]in (measured with fluorescent dyes)
2. Exogenous buffers EGTA e BAPTA reduce the facilitation

But:
increase of residual Ca2+ per AP (about 1 uM) is too small to explain the increase
in Prelease (cf up to 5 times facilitation of the EPSP at the 2° AP), assuming that
residual Ca2+ acts on the Ca-sensor for rapid release (synaptotagmin).

Different high-affinity effectors of residual Ca2+ have been hypothesized:

1- High-affinity Ca-sensors which either modulate vesicle release or facilitate
presynaptic CaV channels
2- Presynaptic fast Ca buffers (e.g. parvalbumin, calbindin)
 The presynaptic CaV2 channels
have a CaM and/or nCaS
binding site in the C-terminus.
Binding of Ca2+ to CaM or
nCaS modulates the channel
open probability

CaV2.1 channels show both Ca-

dependent facilitation and Ca-
dependent inactivation,
whereas CaV2.2 and CaV2.3
channels show only Ca-
dependent inactivation

nCaS = neuronal Ca sensors

have 4 EF hands organized
like in CaM, but at least one of
the two N-terminal EF hands
Catterall and Few (2008) Neuron is non-functional in Ca binding
 Modulation of CaV2.1 channels by CaM

Ca2+ binding to CaM mediates both Ca-dependent facilitation (due to Ca2+ binding at C terminal of
CaM) and Ca-dependent inactivation (due to Ca2+ binding at CaM N-terminal) of CaV2.1 channels.
Intracellular BAPTA eliminates both Ca-dependent faciliatation and inactivation, whereas EGTA
eliminates only Ca-dependent inactivation-Ca binds more rapidly to C- than N-terminal of CaM.

The two lobes of CaM interact differently with the two CaM binding sites at the C terminal of CaV2.1
channels

Catterall and Few (2008) Neuron

 Modulation of CaV2.1 channels by nCaS

nCaS are similar enough to displace CaM from shared binding sites in the C terminus of CaV2.1
channels, but different enough to confer distinct form of regulation

The differential expression and different actions of nCaS on CaV2.1 channels at different synapses
may contribute to the different short-term synaptic plasticity properties

Cf also interation of CaMKII with CaV2.1:

it slows inactivation and shifts st.st inactivation (does not require catalytic activity)

Catterall and Few (2008) Neuron

 Short-term synaptic plasticity during 100
Hz train of APs at the Calyx of Held
synapse in wild-type (WT) and CaV2.1-/-
(KO) mice (1 mM Ca2+)
While in WT mice, there is
facilitation of the EPSC during
the first APs in the train
followed by depression, in KO
mice (CaV2.1-/-) there is only
depression.

In KO mice, synaptic
transmission (EPSC amplitude
elicited by the 1st AP) is not
much impaired because the
CaV2.2 channels compensate
the lack of CaV2.1 channels
(i.e. substitute CaV2.1 at the
active zones). However,
interaction with CaM (nCaS)
does not lead to facilitation of
the CaV2.2 channels, and
hence they cannot
compensate the lack of
CaV2.1-dependent facilitation
of the EPSC in KO mice
Also augmentation and PTP depend on residual Ca

Prolonged increase in [Ca]in (after prolonged stimulation) may be due to:

1. reduced activity of Na/Ca exchanger (that may even revert during
tetanic stimulation) due to reduced Na gradient
2. Saturation of all buffers and filling of Ca stores (ER and mitochondria)
during tetanic stimulation followed by slow Ca efflux from internal Ca
stores

Ca-dependent facilitation of Ca channels may contribute to

augmentation but not to PTP (controversial? )

Other Ca2+ effectors mediate PTP: e.g. PKC (which has been shown to
increase the affinity of the Ca-sensor in Calyx of Held and also to
increase the open probability of presynaptic CaV channels).