Synaptic Plasticity

The term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse.

Facilitation:

The amplitude of the postsynaptic response increases when the postsynaptic cell is activated several times in quick succession

Important Questions:

1) Presynaptic or Postsynaptic?

2) Underlying Mechanisms?

Time Course of Activity Induced Changes

SHORT TERM CHANGES

Facilitation appears instantly, and is of short duration (100 ms)

Depression recovers and Augmentation dissipates within 10 seconds

Post-tetanic potentiation (PTP) can last for more than 10 minutes

LONG TERM CHANGES

Long-term potentiation (LTP) and Long-term Depression (LTD) last from minutes to beyond 10 hours

Synaptic plasticity is classified according to the duration over which the effect

persists.

Most extensively studied at synapses in the peripheral nervous system (chick ciliary ganglion, skeletal muscle)

Changes have also been demonstrated throughout the CNS

Facilitation Augmentation Post-tetanic Potentiation (PTP) Depression

Typically last for periods ranging from milliseconds (facilitation) to tens of minutes (PTP).

Short-term Changes in Signaling

Facilitation of Transmitter Release

Most immediate effect of repetitive stimulation is synaptic facilitation

Amplitudes of EPPs increase progressively

The effect outlasts the stimulus train

Frog NMJ Low Ca2+

Cause: increased mean number of quanta of transmitter released by the presynaptic terminal, probably by increasing the probability of release and perhaps increasing the number of release sites.

Augmentation of Synaptic Transmission

Slower phase of facilitation

Increase in synaptic potential amplitude comes on more slowly than facilitation

Decays over a much longer time period (time constant of 5-10s)

Post-Tetanic Potentiation (PTP)

Relatively long train of high frequency stimuli (Tetanus)

Refers to increased transmitter (ACh) release from presynaptic terminal due to prior stimulation (similar to facilitation and augmentation)

Differs from facilitation and augmentation in that its onset is considerably delayed (reaches maximum several seconds after stimulation

ceases, lasts for tens of minutes

Blocked by removal of calcium from bathing solution, but PTP occurs in the presence of TTX (w/ depolarizing pulses)

Chick ciliary ganglion

Curarized

The frog neuromuscular junction (NMJ) provides an excellent model for studying the role of receptors in synaptic transmission. The preparation has a large postsynaptic element, making it relatively easy to monitor changes in synaptic transmission in the form of end plate potentials (EPPs). Unlike action potentials, EPPs are not all-or-none responses; instead, they reflect small changes in synaptic transmission. To observe EPPs, antagonists must be applied to the NMJ to compete with neurotransmitter binding to postsynaptic receptors. This competition prevents the depolarization of the postsynaptic membrane from reaching threshold and thus, eliminates action potentials.

Curare is an example of a non-depolarizing muscle relaxant which blocks the nicotinic receptors, one of the two types of cholinergic (acetylcholine) receptors on the post synaptic membrane of the neuromuscular junction.

Depression of Transmitter Release

Synaptic depression can occur if the number of quanta released by a train is large

Amplitudes of EPPs decrease progressively with repetitive stimulation

This effect also outlasts the stimulus train (not shown)

Frog NMJ High Ca2+

Thought to be caused by depletion of vesicles from the presynaptic terminal during the conditioning train, and reduced release efficacy.

Curarized

Short Term Synaptic Plasticity Synaptic enhancement (facilitation, augmentation,

potentiation) ALL presynaptic mechanisms Increase in mean number of transmitter quanta without change in

quantal size or postsynaptic effectivenessIncreased probability of release and perhaps an increased number of release sites

Crucial role of calciumResidual presynaptic intracellular calcium

Synaptic depression MOSTLY presynaptic Depletion of pool of vesicles Decrease in number of transmitter quanta

Decrease in probability of release and perhaps a reduced release efficacy

Long-term Changes in Signaling

In the CNS, repetitive activity produces changes in synaptic efficiency that last much longer than seen at peripheral synapses - ranging from minutes to hours.

Hippocampal LTP – best studied of any form of plasticity. Much of the research predicated on assumption that hippocampal LTP is the mechanism for learning.

Cortex – both LTP and LTD of pyramidal cell excitatory synapses

Amygdala – LTP closely linked to fear conditioning

Cerebellum – mostly LTD of Purkinje cell EPSPs. Some LTP at Purkinje cell excitatory synapses and LTP of inhibitory synapses

May represent neural substrates for learning and memory

Long-Term Potentiation Long-Term Depression

LTP and LTDin vitro vs. in vivo

Acute Brain Slice Prep, Slice culture, Co-Cultured cells

Limitations – mimics an intact system removal of normal inputs and milieu addition of blockers such as picrotoxin or tetrodotoxin lack normal outputs

Advantages – clear and interpretable response Single EPSP/IPSP is unequivocal – it’s there or it isn’t No “contamination” from other inputs

Intact anesthetized or freely moving animal

Don’t know “effective” stimulation Can study effects of stimulation on behavior

Long-term Potentiation

First described by Bliss and Lomo (1973) at glutamatergic synapses in the hippocampal formation.

High frequency stimulation of inputs to dentate gyrus cells produces an increase in the amplitude of EPSPs lasting for hours or days.

Homosynaptic LTP

The LTP effect also observed in neocortex.

Why the hippocampus?

Long-term Potentiation in CA1

Requires only a brief tetanus, is input specific, and can last many weeks

Associative LTP and

Learning?

Associative LTP is the strengthening of the connection between two neurons that have been

simultaneously active

Associative LTP Source

“B”

Source“A”

Source“C”

Mechanism(s) for LTP in CA1

Increased effectiveness of existing postsynaptic AMPA receptors, perhaps by phosphorylation. PKC phosphorylation of the AMPA receptor changes the protein in some way that increases the ionic conductance of the channel.

Insertion of completely new AMPA receptors into the membrane

Changes to the structure of the synapse- new buds form on postsynaptic dendrites, axons “sprout” and form multiple synapses.

Significance of Changes in Synaptic Efficacy

LTP (and LTD) are of particular interest because learning and memory are thought to involve long-term changes in synaptic efficacy.

A number of correlations have been shown between spatial learning in intact animals and LTP in hippocampal slices (ie., both blocked by NMDA or mGlu Receptor antagonists)

LTP in amygdala strongly associated with aversive (“fear”) conditioning • rats trained to associate foot shock with a sound exhibit an exaggerated auditory startle reflex• cells in the amygdala display LTP-like increase in their synaptic

responses to stimulation of auditory inputs. • both are blocked by NMDA receptor antagonists.

Linden & Connor, 1995

Types of Long-term Depression

Cerebellar Anatomy

EXCITATORY

Parallel Fibers (gr c.)

Climbing Fibers

INHIBITORY

Purkinje Cells

Stellate Cells

Basket Cells

Long-term Depression in the Cerebellum

After pairing, there is an LTD of the responseto parallel fiber stimulation

Mechanism of LTD in the Cerebellum

AMPA receptors are internalized: Postsynaptic effect

X = no LTP

CF activates Purkinje Cell, Na+ entry depolarizes the dendrite, and voltage-gated Ca2+ channels are activated.

PF activation (glutamate) also increases Na+ entry, through AMPA receptors. The glutamate also directly activates mGluR’s in the membrane. This generates DAG which activates PKC. PKC phosphorylates proteins--somehow leading to a decreased number of AMPA receptors in the postsynaptic membrane.

“Hebbian Rules” for Synaptic ModificationDonald Hebb

(1940s)

When the presynaptic axon is active, and at the same time the postsynaptic neuron is strongly activated by other inputs, then the synapse formed by the presynaptic axon is strengthened

“Neurons that fire together wire together”

When the presynaptic axon is active, and at the same time the postsynaptic neuron is weakly activated by other inputs, then the synapse formed by the presynaptic axon is weakened

“Neurons that fire out of sync lose their link”