LONG-TERM POTENTIATION (LTP)Introduction

LTP as a candidate mechanism for the activity-dependent change in the strength of synaptic connections LTP is a persistent increase in synaptic strength (as measured by the amplitude of the EPSP) that can be rapidly induced by brief neural activity.

Anatomical background for Hippocampus

1. two interlocking C-shaped regions (the hippocampus and the dentate gurus),

2. main inputs: entorhinal cortex 3. three major afferent pathways (subiculum -> CA1)

• Perforant pathway (subiculum -> granule cells in dentate gyrus) • Mossy fiber pathway (axons of the granule cells -> pyramidal cells

in the CA3) • Schaffer collaterals (pyramidal cells in the CA3 -> pyramidal cells

in the CA1)

• Perforant pathway (subiculum -> granule cells in dentate gyrus) • Mossy fiber pathway (axons of the granule cells -> pyramidal cells in the CA3) • Schaffer collaterals (pyramidal cells in the CA3 -> pyramidal cells in the CA1)

entorhinal cortex

subiculumdentate gyrus

CA3 CA1

Perforant pathway

Mossy fiber pathway

Schaffer collaterals

The initial finding by Timothy Bliss and Terje Lomo (1973) •Anaesthetized rabbit •Brief, high-frequency stimulation of the perforant pathway input to the dentate gyrus produced a long lasting enhancement of the extracellular recorded field potential.

Recording techniques In vivo (in awake and freely moving animals, or in anesthetized animals) in vitro (slice preparations) Extracellar recordings intracellular recordings

Experimental designStimulation of a bundle of presynaptic axons recording of monosynaptic EPSP

Typical results for induction of LTP

before

after

The "classical properties" of LTP

Cooperativity The probability of inducing LTP, or the magnitude of the resulting change, increases with the number of stimulated afferents.

Associativity• associativity was shown in preparations in which two distinct axonal inputs converged onto the same postsynaptic target • Concurrent stimulation of weak and strong synapses to a given neuron strengthens the weak ones.

Input specificity LTP is restricted to only the inputs that received the tenanic (high-frequency) stimulation

Underlying molecular mechanisms 1. Introduction

1. LTP requires some sort of additive effect 1. High-frequency stimulation

2. Activation of synapses and depolarization of the postsynaptic neuron must occur at the same time

2. LTP (in area CA1) depends on certain changes at glutamate synapses,

3. Types of glutamate receptors 1. NMDA receptors 2. Non-NMDA receptors, AMPA

1. At non-NMDA receptors, 1. glutamate is excitatory 2. Open channels for sodium ions

At NMDA receptors

BEFORE1. Controls a calcium ion channel 2. glutamate is neither excitatory nor inhibitory 3. Ion channel is blocked by magnesium ions

DURING INDUCTION 1. Activation of NMDA receptors requires both glutamate and

depolarization, which lead to the removal of magnesium ions 2. The NMDA receptors now respond actively to glutamate and

admit large amount of Ca2+ through their channels 3. After induction of LTP, transmission at non-NMDA receptors is

facilitated (entry of Na+)

LTP is induced via a cascade of neurochemical steps1. The entry of Ca2+ ions into neurons activates some protein

kinases (which are enzymes that catalyze phosphorylation, the addition of phosphate groups to protein molecules).

2. One of the kinase, Calcium-calmodulin kinase (CaM kinase) remains activated once it is put into that state by Ca2+, even if the level of Ca2+ subsequently falls

3. The activated protein kinases also trigger the synthesis of proteins 1. activate cAMP responsive element-binding protein (CREB) 2. CREB -> production of the transcription (mRNA) of

immediate early genes (IEGs) -> regulate the expression of particular late effector genes (LEGs) -> synthesis of proteins

4. Induction of LTP requires a retrograde signal, from the postsynaptic neuron to the presynaptic neuron