vertebrate models of learning synaptic plasticity in the hippocampus –ltp and ltd key to forming...

Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus– LTP and LTD

• Key to forming declarative memories in the brain

– Bliss and Lomo• High frequency electrical stimulation of excitatory

pathway

– Anatomy of Hippocampus• Brain slice preparation: Study of LTD and LTP

Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus– Anatomy of the Hippocampus

Hippocampus:

Dentate Gyrus

Ammon’s horn (4 divisions: CA1, CA2, CA3, CA4; (CA stands for cornu Ammonis, Latin for “Ammon’s horn.”

Perforant path

Mossy fibers

Schaffer collateral

Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus– Properties of LTP in CA1

LTP first shown in perforant path synapses on CA3 neurons; now in Schaffer collateral synapse on CA1 neurons.

Test stimulus versus tetanus, a brief burst of high-frequency stimulation.

LTP is input specific.

LTP - hippocampus

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LTP• Form of plasticity can be induced by 1-s of

tetanus

• LTP in CA1 in awake animals can last many weeks, maybe a lifetime.

• CA1 neurons must be active during tetanus for LTP

• Temporal & spatial summation required

• Important for associations

Vertebrate Models of Learning• Synaptic Plasticity in the Hippocampus

(Cont’d)– Mechanisms of LTP in CA1

• Glutamate receptors mediate excitatory synaptic transmission

– AMPARs» Na+ ions enter to cause

EPSP– NDMARs

» Ca++ entry only if depolarized enough to displace Mg++ ions that clog channel

» Ca - PKC & CaMKII» Inhibition of kinases

blocks LTP– More AMPARs, more

spines

Vertebrate Models of Learning• Synaptic Plasticity in the Hippocampus

– Long-Term Depression in CA1 (decrease synaptic effectiveness)– Tetanic stimulation at low frequencies (1-5 Hz) produces LTD

Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus (Cont’d)– BCM theory

• Named after authors: Bienenstock, Cooper, Munro at Brown University

• When the postsynaptic cell is weakly depolarized by other inputs: Active synapses undergo LTD instead of LTP

• Accounts for bidirectional synaptic changes (up or down)

• LTP adding phosphate groups,• LTD removing phosphate groups

w protein phosphotases

Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus (Cont’d)– LTP, LTD, and Glutamate Receptor

Trafficking • Stable synaptic transmission: AMPA receptors are

replaced maintaining the same number• LTD and LTP disrupt equilibrium• Bidirectional regulation of phosphorylation

Vertebrate Models of Learning

• LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

Vertebrate Models of Learning• LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)• Egg carton model of AMPA receptor trafficking at synapse• Size of scaffold - slot proteins• Scaffold like egg carton• Slot proteins form egg cups• AMPARs are the eggs• LTP increase scaffold• LTD decrease scaffold• PSD-95 may be egg carton• New AMPARs have GluR1

The Molecular Basis of Long-Term Memory

• Phosphorylation as a long term mechanism: Problematic (transient and turnover rates)

• Persistently Active Protein Kinases– Phosphorylation maintained:

Kinases stay “on” • CaMKII and LTP

– Molecular switch hypothesis

The Molecular Basis of Long-Term Memory

• Protein Synthesis– Requirement of long-term memory

• Synthesis of new protein

– Protein Synthesis and Memory Consolidation • Protein synthesis inhibitors

– Deficits in learning and memory

– CREB and Memory• CREB: Cyclic AMP response element binding

protein

The Molecular Basis of Long-Term Memory

• Protein Synthesis (Cont’d)– Structural Plasticity and Memory

• Long-term memory associated with formation of new synapses

• Rat in complex environment: Shows increase in number of neuron synapses by about 25%

Concluding Remarks

• Learning and memory– Occur at synapses

• Unique features of Ca2+

– Critical for neurotransmitter secretion and muscle contraction, every form of synaptic plasticity

– Charge-carrying ion plus a potent second messenger

• Can couple electrical activity with long-term changes in brain