Chapter 25: Molecular Mechanisms: learning/memory

LTP in hippocampal slices: an ideal memory mechanism

rapid onset, activity dependent, long-lasting increase in synaptic strength

induced by high frequency stimulation

first found in hippocampus (already implicated in memory) also occurs in cortex, amygdala, striatum, other regions

synapse-specific

associative/cooperative (Hebb's rule)

Early and late phase LTP

E-LTP: 1 tetanus, response DECAYS QUICKLY

L-LTP: more stimulation, SUSTAINED response

Properties of LTP in CA1

to induce LTP, input 1 axons are given tetanus (burst of high frequency stimulation)

LTP is INPUT SPECIFIC: input 2 does NOT show LTP

What is required for LTP

synapses be active at the SAME TIME that the postsynaptic CA1 neuron is STRONGLY DEPOLARIZED

To achieve necessary DEPOLARIZATION with tetanus

high frequency stimulation causes TEMPORAL SUMMATION

enough synapses must be active to cause SPATIAL SUMMATION (cooperativity)

NMDA conducts Ca++ only when glutamate binds and postsynaptic is depolarized to remove Mg++

Without NMDA, there's no LTP involved

APV blocks NMDA receptors --> no LTP

AMPA receptors provide depolarization with, through temporal and spatial summation, may OPEN some NMDA receptors

Glutamate receptor trafficking

AMPA receptors are CONTINUALLY being ADDED and REMOVED from the membrane

LTD and LTP disrupt equilibrium and lead to net increase or decrease in AMPA receptors in membrane

LTP requires MORE synaptic capacity for AMPA receptors and more AMPA receptors

LTD requires LESS synaptic capacity and loss of AMPA receptors

Kinases and AMPA trafficking

Short term plasticity: covalent modification of preexisting proteins (PHOSPHORYLATION of channels or receptors)

CamKII is the most important kinase for short-term LTP

anything kinases do, phosphates can UNDO

phosphorylation of preexisting proteins cannot account for long term memory

Memory consolidation: PERSISTENTLY active protein kinases

required for LTP IN CA1: entry of Ca++ into postsynaptic cell AND activation of CamKII

CamKII subunits connected by a hinge: catalytic and regulatory regions

catalytic region (performs phosphorylation reaction)

regulatory region

Hinge of CamKII is "off" when REGULATORY region COVERS CATALYTIC region

Hinge opens (CamKII activated) by Ca++ bound calmodulin (second messenger)

can phosphorylate AMPA receptors

LARGE increases in Ca++ (LTP) can cause AUTOPHOSPHORYLATION and PERSISTENT, permanent activation of CamKII

Long term plasticity (and memory) requires activation of gene transcription and SYNTHESIS of new proteins, via PKA and/or CaMKII and CREB

1st step in protein synthesis: generation of mRNA transcript of a gene

CREB binds to specific segments of DNA (CREs) (Regulates expression of neighboring genes)

2 forms of CREB

CREB-2: REPRESSES gene expression when it binds to CRE

CREB-1 ACTIVATES transcription (only when it's phosphorylated by protein kinase A)

Aplysia californica

Behavior: gill-withdrawal reflex: gill retracts when water is sprayed on siphon

Associative long-term learning in Aplysia: Classical conditioning

weak stimulus to siphon (conditioned stimulus) is paired with shock to the tail (unconditioned stimulus)

learn to ASSOCIATE stimulus with shock and RETRACT gill

Coincidence detection by Aplysia Californica type I

stimulus to the tail activates serotonergic modulatory neurons that influence SYNAPTIC TRANSMISSION at sensory-motor synapse

serotonin stimulates RISE in cAMP and ACTIVATION of PKA

causing INCREASE release of GLUTAMATE when siphon is touched

REPEATED ACTIVATION of serotonergic modulatory neurons cause long-term SENSITIZATION, requiring new gene expression and protein synthesis

What BLOCKS long-term memory in Aplysia

serotonin antagonists

PKA, CaMKII or PKC inhibitors

transcription inhibiotrs

protein synthesis inhibitors

reduction in CREB activity

What do CREB-driven genes DO?

facilitate formation of new synapses

add new Ca++ channels to SN

increase persistent activation of protein kinase A

Add new AMPA-type receptors to MN

stabilize newly added AMPA receptors

Classical Conditioning and fear

when a conditioned stimulus (tone) is paired with unconditioned stimulus (shock)

tone is CONDITIONED to produce fear (conditioned response)

this cued fear depends on AMYGDALA

channel rhodopsin can be used as a stand-in for the tone

main advantage of using CHR

being able to reliably fire the same neurons in repeated rounds

induce LTD in those same neurons

conditioned fear disappears along with decrease synaptic strength (bring it back with LTP)