Neural Plasticity: Long-term Potentiation Lesson 15

Neural Plasticity n Nervous System is malleable l learning occurs l Structural changes at synapses n Changes in synaptic efficiency l Long-term potentiation l Long-term depression n LTP & LTD throughout brain l Many different mechanisms ~

Neural Mechanism of Memory n Donald Hebb n Short-term Memory l Change in neural activity l not structural l temporary n Reverberatory Circuits - l cortical loops of activity ~

Reverberating Loops n Maintains neural activity for a period l Activity decays ~

Hebb’s Postulate n Long-Term Memory l required structural change in brain l relatively permanent n Hebb Synapse l use strengthens synaptic efficiency l concurrent activity required pre- & postsynaptic neurons ~

Long-term Potentiation n According to Hebb rule l use strengthens synaptic connection n Synaptic facilitation l Structural changes l Simultaneous activity n Experimentally produced l hippocampal slices l associative learning also ~

Inducing LTP Stimulating electrode Record Presynaptic neuron Postsynaptic neuron

-70mv - + Postsynaptic Potential 1. Single Stimulation (AP) 2. High frequency stimulation 3. Single stimulation

n Pattern Of Stimulation l Brief, high frequency stimulation l > 10 Hz (10 AP/sec) n LTP Duration l Hippocampal slices: 40 hours l Intact animals: Up to a year ~ Experimentally-induced LTP

n Associative learning l Respondent & Operant learning n Strengthening of association l Strong link: US  Response (UR) l Weak link: CS  Response (CR) n Concurrent activity l CS, US  Response l LTP in CS (strengthened)~ LTP & Associative Learning

W1W1 W2W2 S R W1W1 W2W2 S US LTP: Associative n Before Learning l Stim S  AP in R l W 1 or W 2  no AP in R

W1W1 W2W2 S R W1W1 W2W2 S US LTP: Associative n Induction l Paired: S + W 1  AP LTP in W 1 l Unpaired: W 2  no AP

W1W1 W2W2 S R W1W1 W2W2 S US LTP: Associative n After LTP l W 1 alone  AP in R l W 2 alone  no AP in R

LTP: Molecular Mechanisms n Presynaptic & Postsynaptic changes n HC  Glutamate l excitatory n 2 postsynaptic receptor subtypes l AMPA  Na+ l NMDA  Ca++ n Glu ligand for both ~

NMDA Receptor n N-methyl-D-aspartate n Glu binding opens channel? l required, but not sufficient n Membrane must be depolarized l before Glu binds ~

Single Action Potential n Glu  AMPA  -amino-3-hydroxyl-5-methyl-4- isoxazole-propionate l depolarization n Glu  NMDA l does not open l Mg++ blocks channel l Little Ca++ into postsynaptic cell n Followed by more APs ~

AMPA NMDA Mg G Ca++ Na+ G G G

NMDA Mg G Ca++ G AMPA Na+ G G

NMDA Mg GG Ca++ AMPA Na+ G G

NMDA G Ca++ G Mg AMPA Na+ G G

Activation of NMDA-R n Ca++ channel l chemically-gated l voltage-gated Mg++ blocks channel n  Ca++ influx  post-synaptic changes l strengthens synapse ~

Ca 2+ -mediated Effects n Activation of protein kinases l Protein Kinase C (PKC) l Ca 2+ /calmodulin-dependent protein kinase (CaMKII) l Targets: AMPA-R & other signaling proteins n CaMKII important role l Block CaMKII  No LTP l Self-phosphorylation   LTP duration ~

LTP: Postsynaptic Changes n Receptor synthesis n More synapses n Shape of dendritic spines n Nitric Oxide synthesis ~

Presynaptic Axon Terminal Dendritic Spine Before LTP

Presynaptic Axon Terminal Dendritic Spine After LTP less Fodrin Less resistance

Nitric Oxide - NO n Retrograde messenger l Hi conc.  poisonous gas n Hi lipid solubility l storage? n Synthesis on demand l Ca++  NO synthase  NO n Increases NT synthesis in presynaptic neuron l more released during AP ~

G Ca++ G NOSNO cGMP Glu G G