Synaptic Plasticity

3. Synaptic Plasticity

4. 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: • Presynaptic or Postsynaptic? • Underlying Mechanisms?

5. Time Course of Activity Induced Changes Synaptic plasticity is classified according to the duration over which the effect persists. SHORT TERM CHANGESFacilitation appears instantly, and is of short duration (100 ms)Depression recovers and Augmentation dissipates within 10 secondsPost-tetanic potentiation (PTP) can last for more than 10 minutesLONG TERM CHANGESLong-term potentiation (LTP) and Long-term Depression (LTD) last from minutes to beyond 10 hours

6. Short-term Changes in Signaling • 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).

7. 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.

8. 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)

9. 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) Curarized Chick ciliary ganglion

10. 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.

11. 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) Curarized Frog NMJ High Ca2+ Thought to be caused by depletion of vesicles from the presynaptic terminal during the conditioning train, and reduced release efficacy.

12. 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 effectiveness Increased probability of release and perhaps an increased number of release sites • Crucial role of calcium Residual 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

13. 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. HippocampalLTP – 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

14. 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

15. Long-term Potentiation Why the hippocampus? • 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.

16. Long-term Potentiation in CA1 Requires only a brief tetanus, is input specific, and can last many weeks

17. Associative LTP and Learning? Associative LTP is the strengthening of the connection between two neurons that have been simultaneously active

18. Source “A” Source “C” Source “B” Associative LTP

19. 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.

20. 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.

21. Types of Long-term Depression Linden & Connor, 1995

22. EXCITATORY Parallel Fibers (gr c.) Climbing Fibers INHIBITORY Purkinje Cells Stellate Cells Basket Cells Cerebellar Anatomy

23. Long-term Depression in the Cerebellum After pairing, there is an LTD of the response to parallel fiber stimulation

24. X = no LTP Mechanism of LTD in the Cerebellum AMPA receptors are internalized: Postsynaptic effect 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.

25. “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”