Neural Plasticity:Long-term

PotentiationLesson 15

Neural Plasticity Nervous System is malleable

learning occurs Structural changes at synapses

Changes in synaptic efficiency Long-term potentiation Long-term depression

LTP & LTD throughout brain Many different mechanisms ~

Neural Mechanism of Memory

Donald Hebb Short-term Memory

Change in neural activity not structural temporary

Reverberatory Circuits - cortical loops of activity ~

Reverberating Loops

Maintains neural activity for a period Activity decays ~

Hebb’s Postulate

Long-Term Memory required structural change in brain relatively permanent

Hebb Synapse use strengthens synaptic efficiency concurrent activity required

• pre- & postsynaptic neurons ~

Long-term Potentiation

According to Hebb rule use strengthens synaptic connection

Synaptic facilitation Structural changes Simultaneous activity

Experimentally produced hippocampal slices associative learning also ~

Inducing LTP

Stimulating electrode

Record

Presynapticneuron

Postsynapticneuron

-70mv

-

+

Postsynaptic Potential

1. Single Stimulation (AP)

2. High frequency stimulation

3. Single stimulation

Pattern Of Stimulation Brief, high frequency stimulation > 10 Hz (10 AP/sec)

LTP Duration Hippocampal slices: 40 hours Intact animals: Up to a year ~

Experimentally-induced LTP

Associative learning Respondent & Operant learning

Strengthening of association Strong link: US Response (UR) Weak link: CS Response (CR)

Concurrent activity CS, US Response LTP in CS (strengthened)~

LTP & Associative Learning

W1

W2

S R

W1

W2

SUS

LTP: Associative Before Learning

Stim S AP in R W1 or W2 no AP in R

W1

W2

S R

W1

W2

SUS

LTP: Associative Induction

Paired: S + W1 AP

• LTP in W1

Unpaired: W2 no AP

W1

W2

S R

W1

W2

SUS

LTP: Associative After LTP

W1 alone AP in R

W2 alone no AP in R

LTP: Molecular Mechanisms

Presynaptic & Postsynaptic changes HC Glutamate

excitatory 2 postsynaptic receptor subtypes

AMPA Na+ NMDA Ca++

Glu ligand for both ~

NMDA Receptor

N-methyl-D-aspartate Glu binding opens channel?

required, but not sufficient Membrane must be depolarized

before Glu binds ~

Single Action Potential

Glu AMPA-amino-3-hydroxyl-5-methyl-4-

isoxazole-propionate depolarization

Glu NMDA does not open Mg++ blocks channel Little Ca++ into postsynaptic cell

Followed by more APs ~

AMPA NMDAMg

G

Ca++Na+

G GG

NMDAMg

G

Ca++

GAMPA

Na+

GG

NMDA

MgG G

Ca++

AMPA

Na+GG

NMDAG

Ca++

G

Mg

AMPA

Na+

GG

Activation of NMDA-R

Ca++ channel chemically-gated voltage-gated

Mg++ blocks channel Ca++ influx post-synaptic changes

strengthens synapse ~

Ca2+-mediated Effects

Activation of protein kinases Protein Kinase C (PKC) Ca2+/calmodulin-dependent protein

kinase (CaMKII) Targets: AMPA-R & other signaling

proteins CaMKII important role

Block CaMKII No LTP Self-phosphorylation LTP duration ~

LTP: Postsynaptic Changes

Receptor synthesis More synapses Shape of dendritic spines Nitric Oxide synthesis ~

PresynapticAxon Terminal

Dendritic Spine

Before LTP

PresynapticAxon Terminal

Dendritic Spine

After LTP

less Fodrin

Less resistance

Nitric Oxide - NO

Retrograde messenger Hi conc. poisonous gas

Hi lipid solubility storage?

Synthesis on demand Ca++ NO synthase NO

Increases NT synthesis in presynaptic neuron more released during AP ~

G Ca++

G

Ca++NOSNO

NO cGMP Glu

GG