lecture - neuroscience, 4e

Chapter 8: Synaptic Plasticity

April 8, 2010

Synaptic Plasticity

Definition• Change in strength of synapse caused

by training• Activity dependent change in amplitude

of PSC Importance

• Thought to be mechanism underlying learning and memory

• Involved in development of neural circuits

Outline

Major classification along two dimensions• Time frame

Short term plasticityLong term plasticity

• MechanismsPre-synapticPost-synaptic

Relationship to learning and memory• Invertebrate models• Mammalian models

How to Measure Synaptic Plasticity

Intracellular • Size of evoked EPSP or EPSC• Frequency of spontaneous EPSCs

Extracellular (in Hippocampus)• Fields Potentials generated

simultaneous firing of aligned neurons• Slope of population EPSP

Proportional to peak synaptic conductance

Short Term Synaptic Plasticity

Short term increase or decrease in synaptic strength

• not thought to be involved in memory storage• duration less than tens of minutes

Increase in synaptic strength• Facilitation• Augmentation• Potentiation

Decrease in synaptic strength• Depression

All are pre-synaptic

Short Term Synaptic Plasticity-Facilitation

Increase in PSP amplitude caused by brief period of high-frequency stimulation

• Two or more AP within millisecondsRapid onsetEffect decays rapidly after stimulation

offset• Lasts only tens of msec

Mechanism is accumulation of calcium in axon terminal

• Calcium clearance is slower than interspike interval

• Residual partial binding to synaptotagmin

Short Term Synaptic Plasticity-Facilitation

This shows that the second PSP is larger than the first, when the action potentials are 10 msec apart

Short Term Synaptic Plasticity-Facilitation

This shows that facilitation decreases as the interval between action potentials increases

Short Term Synaptic Plasticity-Augmentation

Steadily increasing, cumulative enhancement of neurotransmitter release during a train of AP

Onset and Duration – 100s of ms to seconds

Mechanism is accumulation of calcium in axon terminal

• Protein target of calcium is unknown

Short Term Synaptic Plasticity-Augmentation

This shows that under low calcium, the size of the PSP increases over several seconds of stimulation

Short Term Synaptic Plasticity-Potentiation

Post-tetanic potentiation• Increase in PSC that is longer lasting

than augmentationOnset and Duration - seconds to

minutes• Requires more prolonged stimulation

than augmentation• Mechanism is calcium mediated

release of vesicles from reserve poolPhosphorylation of synapsin (by

CaMKinase)

Short Term Synaptic Plasticity-Potentiation

This shows that an enhancement of the PSP lasts for several minutes after a very strong (tetanizing) stimulation

Short Term Synaptic Plasticity-Depression

Decrease in neurotransmitter release during sustained synaptic activity

Amount of depression depends on the amount of neurotransmitter released previously

Mechanisms thought to be depletion of vesicles

• Rate of release decreases till release rate balances replenishment rate

• More depression when reserve pool is smaller

• More depression when release probability is higher

Short Term Synaptic Plasticity-Depression

Under normal calcium, stimulation for several seconds produces decrease in PSP amplitude.

The amount of depression is inversely related to amount of transmitter release

0 5 10 15 20 25

Short Term Synaptic Plasticity

Tendency of facilitate or depress differs between synapses

Both facilitation and depression can occur depending on characteristics of spike trains

Irregular spike trains (physiological) can produce complex pattern of depression and facilitation

Generally observed that high p synapses exhibit paired pulse depression, and low p synapses exhibit paired pulse facilitation

Combinations on Short-Term Plasticity at the Neuromuscular Synapse

During train of AP, initial PSPs (from 50-100 ms) are increasing in size

• FacililtationPSPs from 100 to

250 ms are decreasing in size

• Depression

Combinations on Short-Term Plasticity at the Neuromuscular Synapse

During interval• Decay of

Depression, facilitation, and augmentation

• Build up of Potentiation

Larger PSP observed 30 sec later

Learning and Memory

Learning: adaptive change in behavior caused by experience

• Adaptive: survival value for animal• Change: measurable difference,

selective to appropriate part of organism, independent of growth or injury

• Behavior: must involve central systemsMemory: storage and recall of previous

experiences; necessary for learning

Types of Learning and Memory

Non-declarative or Implicit memory• Non associative learning:

HabituationDensitization

• Associative learning:Classical ConditioningOperant Conditioning

Declarative or Explicit Memory• Memory for events and facts• Talking about what happened before

Implicit Learning and Memory

Non associative learning:• Habituation

Decrease in behavioral response that occurs during repeated presentation of stimulus.

• SensitizationEnhancement of reflex response by

introduction of strong or noxious stimulus

Implicit Learning and Memory

Associative Learning• Classical Conditioning

Repeated presentation of a neutral conditioned stimulus followed (by a fixed interval) by an unconditioned stimulus (that elicits a reflex response) causes a new CS response which mimics the UR

Stimuli presentation are independent of behavior

Learning Behavior in Aplysia

What is Aplysia?• Sea Hare• Kingdom-Animalia• Phylum-Mollusca

Includes squid and clams• Class-Gastropoda (snails and slugs)

Stomach-foot• Order-Opistobranchia

Gilled snails and slugs

Short-term sensitization of the Aplysia gill withdrawal reflex

Value of Aplysia, and other invertebrates is due to small numbers of identifiable neurons

Learning Behavior in Aplysia

Habituation• Light touch to siphon causes withdrawal• Repeated light touch results in smaller

amplitude of withdrawalSensitization

• Electric shock to tail sensitizes animal to siphon touch

• Assessed by measuring amplitude of repeated light touches with and without electric shock

Short-term sensitization and habitulation of the Aplysia gill withdrawal reflex

Sensitization

Habituation

Sensitization of Aplysia gill withdrawal reflex

1 shock produces short term sensitization Four trains of shocks produces long term

sensitization• Always compare to control with no shocks

Synaptic mechanisms underlying short-term sensitization and habituation

Critical neurons in circuit mediating sensitization

• Motor neuron to gillStimulation produces withdrawal

• Sensory neuron to gillReleases glutamate onto motor

neuron• These two neurons constitute two

neuron “reflex” circuit

Synaptic mechanisms underlying short-term sensitization and habituation

Activation of excitatory interneuron increases likelihood of motor neuron firing

Synaptic mechanisms underlying short-term sensitization and habituation

Decrease in PSP from sensory to motor neuron during habituation

• Pre-synaptic decrease in vesicle release

Synaptic mechanisms underlying short-term sensitization and habituation

Critical neurons in circuit mediating sensitization

• Sensory neuron to tailActivated with tail shock

• Modulatory interneuronReceives input from tail sensory

neuronSerotonergic output onto siphon

sensory neuron pre-synaptic terminal

Synaptic mechanisms underlying short-term sensitization and habituation

Modulatory interneuronModulatory interneuron releases serotonin

Synaptic mechanisms underlying short-term sensitization and habituation

Increase in PSP from sensory to motor neuron during sensitization

Synaptic mechanisms underlying short-term sensitization

Sensitization of synapses lasts for 10s of minutes

Mechanism of presynaptic enhancement underlying behavioral sensitization

1. Serotonin is released by modulatory interneuron and binds to GPCR

Mechanism of presynaptic enhancement underlying behavioral sensitization

2. GPCR produces GαsGTP, which binds to Adenylyl Cyclase, which produces cAMP

Mechanism of presynaptic enhancement underlying behavioral sensitization

3. cAMP binds to and activates Protein Kinase A

Mechanism of presynaptic enhancement underlying behavioral sensitization

4. Catalytic subunits of Protein Kinase A phosphorylates potassium channels

Mechanism of presynaptic enhancement underlying behavioral sensitization

5. Decreased opening of potassium channels prolongs the AP, allowing more calcium influx

Mechanism of presynaptic enhancement underlying behavioral sensitization

6. Increased calcium causes more vesicles of transmitter release onto motor neuron

Mechanism of long-term synaptic enhancement

PKA phosphorylates CREB, which binds to CRE, increasing transcription of genes

Mechanism of long-term synaptic enhancement

Ubiquitin hydroxylase stimulates degradation of regulatory subunit of PKA, allowing persistence of free catalytic subunit of PKA

Mechanism of long-term synaptic enhancement

Other genes lead to proliferation of synaptic terminals

• Long term structural changesCytoplasmic polyadenylation element binding

protein (CPE) activates mRNAs enhancing local protein synthesis