lecture - neuroscience, 4e
TRANSCRIPT
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