Long term potentiation

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LONG-TERM POTENTIATION

Kolb, An Introduction to Brain and Behavior, Second Edition – Chapter 5

Role of Synapses in Learning and Memory

• Habituation Response• Sensitization Response

• Long-Term Potentiation and Associative Learning• Learning at the Synapse• Focus on New Research: Dendritic Spines, Small but Mighty

• The Nature of Learning

– Learning:• The process by which experiences change our nervous system and hence

our behaviors• Memories are reconstructed recollections of events and other episodes

encountered during our lives– Types of learning (the basics):

• Classical conditioning:– A learning procedure in which when a stimulus that initially produced no

particular response is followed several times by an unconditioned stimulus that produces a defensive or appetitive response

• Instrumental learning:– A learning procedure whereby the effects of a particular behavior in a

particular situation increase (reinforce) or decrease (punish) the probability of the behavior

• Perceptual learning:– Learning to recognize a particular stimulus

• Motor learning:– Learning to perform a particular motor task (writing)


– Learning:• The process by which experiences change our nervous

system and hence our behaviors.

– Perceptual learning:• Learning to recognize a particular stimulus.

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Associative LearningLinkage of two or more unrelated stimuli to elicit a behavioral response


– Classical conditioning:• A learning procedure; when a stimulus that initially

produces no particular response is followed several times by an unconditioned stimulus that produces a defensive or appetitive response.

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– Instrumental learning:• A learning procedure whereby the effects of a particular

behavior in a particular situation increase (reinforce) or decrease (punish) the probability of the behavior; also called operant conditioning.

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– Reinforcing stimulus:• An appetitive stimulus that follows a particular

behavior and thus makes the behavior become more frequent.

– Punishing stimulus:• An aversive stimulus that follows a particular behavior

and thus makes the behavior become less frequent.

– Motor learning:• Learning to make a new response.

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In – Integrate -- Out

• Learning and Synaptic Plasticity– Induction of Long-Term Potentiation

– Long-term potentiation:• A long-term increase in the excitability of a neuron to

a particular synaptic input caused by repeated high-frequency activity of that input.

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• For decades, researchers have been trying to determine how learning is recorded and stored in the brain

• There is no shortage of theories, but the most influential (and most likely correct) was proposed by Donald Hebb over 50 years ago

• Hebb’s rule:– The cellular basis of learning

involves strengthening of a synapse that is repeatedly active when a postsynaptic neuron fires

– Through repeated pairing, there will be structural and chemical changes resulting in strengthening of active synapses forming a stronger circuit

– This is a form of long term potentiation Fire together = Wire

together


–Hebb rule:• The hypothesis proposed by Donald Hebb that the

cellular basis of learning involves strengthening of a synapse that is repeatedly active when the postsynaptic neuron fires.

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Kolb & Whishaw, An Introduction to Brain and Behavior, Second Edition - Chapter 5

Role of Synapses in Learning and MemoryAssociative Learning

• A strong burst of electrical stimulation applied to the presynaptic neuron produces an increase in the amplitude of the EPSP in the postsynaptic neuron

• First recorded in the hippocampus by Bliss and Lømø in 1973– Field Potential:

• EPSPs from many neurons; recorded with extracellular electrodes

• Learning and Synaptic Plasticity– Induction of Long-Term Potentiation

– Hippocampal formation:• A forebrain structure of the temporal lobe,

constituting an important part of the limbic system; includes the hippocampus proper (Ammon’s horn), dentate gyrus, and subiculum.

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Classical Long Term Potentiation

• Classical or nonassociative long-term potentiation:– A long-term increase in the excitability of a

neuron to a particular synaptic input caused by repeated high-frequency activity of that input

– Usually modeled through two neurons, a presynaptic neuron’s repeatedly providing high frequency of activity to another neuron

• LTP occurs throughout the brain, but a high concentration of LTP occurs in the hippocampus and is believed to play a role in learning and memories 13.6

• Induction of Long-Term Potentiation (LTP)

• Hippocampal formation:– A forebrain structure of the

temporal lobe, constituting an important part of the limbic system

– Hippocampus includes the dentate gyrus, CA fields, and the subiculum

• Dentate gyrus: Part of the hippocampal formation that receives inputs from the entorhinal cortex and projects to the CA3 field of the hippocampus

– Perforant path: The system of axons that travel from the entorhinal cortex to the dentate gyrus

– Granule cells: Receives input from the perforant path and sends axons to the field CA3 of the hippocampus

17Copyright © 2004 Allyn and Bacon

• Learning and Synaptic Plasticity– Induction of Long-Term

Potentiation

– Entorhinal cortex:• A region of the limbic cortex

that provides the major source of input to the hippocampal formation.

– Granule cell:• A small, granular cell; those

found in the dentate gyrus send axons to the field CA3 of the hippocampus.

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Potentiation

– Dentate gyrus:• Part of the hippocampal

formation; receives inputs from the entorhinal cortex and projects to the CA3 field of the hippocampus.

– Perforant path:• The system of axons that

travel from cells in the entorhinal cortex to the dentate gyrus of the hippocampal formation.

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Potentiation

– Field CA3:• Part of the hippocampus;

receives inputs from the dentate gyrus and projects to field CA3.

– Pyramidal cell:• A category of large

neurons with a pyramidal shape; found in the cerebral cortex and Ammon’s horn of the hippocampal formation.

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Potentiation

– Field CA1:• Part of the hippocampus;

receives inputs from field CA3 and projects out of the hippocampal formation via the subiculum.

– Population EPSP:• An evoked potential that

represents the EPSPs of a population of neurons.

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Hippocampus

Dentate gyrus

CA3

CA1Entorhinal CortexSubiculu

m

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• Induction of Long-Term Potentiation

• If the cells of the perforant path are stimulated with rapid bursts of electricity, there will be stronger and stronger EPSPs recorded in the granule cells of the dentate gyrus– This is evidence of LTP– This heightening of activity

lasts over time (up to several months)


Associative Long Term Potentiation

•With this type of LTP, a weak burst of electrical stimulation paired with a strong burst of electrical stimulation will result in an increase in the strength of the electrical stimulation by the weak input over time

•This is consistent with Hebb’s rule

• Role of NMDA Receptors in LTP

– Non-associative LTP requires a high frequency rates of input to produce LTP delivered over a short period of time to dendritic spines of postsynaptic neurons

• The rapid rate of stimulation results in increases postsynaptic membrane depolarization because the previous EPSP has not dissipated, resulting in a summation effect of EPSP

– For LTP to occur, the postsynaptic cell must be depolarized and receiving excitatory input from presynaptic cells

• The reason both these events must be occurring simultaneously is due to the complex nature of the receptor protein that plays a role in LTP, the NMDA receptor

– NMDA receptor:• A specialized ionotropic glutamate receptor that controls a calcium channel

(Ca2+)• Normally, NMDA receptors are blocked by a Mg2+ ion which prevents Ca2+

from entering the channel, even in the presence of the glutamate on the receptor

• However, when the cell is slightly depolarized Mg2+ is ejected AND Ca2+ can enter the cell resulting in depolarization and strengthening of a synaptic connection (or LTP)

• Learning and Synaptic Plasticity– Role of NMDA Receptors

– Associative long-term potentiation:• A long-term potentiation in which concurrent

stimulation of weak and strong synapses to a given neuron strengthens the weak one.

– NMDA receptor:• A specialized ionotropic glutamate receptor that

controls a calcium channel that is normally blocked by Mg2 ions; involved in long-term potentiation.

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• Neurotransmitters and Neuromodulators– Amino Acids– Glutamate

– Glutamate:• An amino acid; the most important excitatory neurotransmitter

in the brain.

– NMDA:_______________?• A drug that serves as a noradrenergic and serotonergic agonist,

also known as “ecstasy”; has excitatory and hallucinogenic effects.

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– NMDA receptor:• A specialized ionotropic glutamate receptor that controls a

calcium channel that is normally blocked by Mg2+ ions; has several other binding sites.

– AMPA receptor:• An ionotropic glutamate receptor that controls a sodium

channel; stimulated by AMPA and blocked by CNQX; the most common glutamate receptor.

AMPA receptor:An ionotropic glutamate receptor that controls a sodium channel; when it’s open, it produces EPSPs

34 Copyright © 2004 Allyn and Bacon

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– Kainate receptor:• An ionotropic glutamate receptor that controls a sodium

channel; stimulated by kainic acid and blocked by CNQX.

– Metabotropic glutamate receptor:• A category of metabotropic receptors sensitive to glutamate.

– AP5:• A drug that blocks the glutamate binding site on NMDA

receptors

AP5:2-Amino-5-phosphonopentanoate; a drug that blocks NMDA receptors.

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Dendritic spike:An action potential that occurs in the

dendrite of some types of pyramidal cells.

• Learning and Synaptic Plasticity– Role of NMDA Receptors

– Dendritic spike:• An action potential that occurs in the dendrite of

some types of pyramidal cells.

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13.3

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41Ready to Learn!

• Presynaptic Facilitation of LTP– Research believe that presynaptic facilitation is also required for LTP

• This may result in an increased release of glutamate from presynaptic cells– Nictric oxide (NO) is a molecule created from a naturally occurring

amino acid present in the brain• NO is used as a messenger in the circulatory system and other parts of the

body• It is a short acting messenger that is quickly degraded in the brain

– Drugs blocking NO seem to prevent development of LTP. Other evidence suggesting NO may be involved in LTP:

• NO is synthesized in cells containing NMDA receptors• NO is synthesized in hippocampal cells, such as the dentate gyrus, CA1,

and CA3– In a way that has not yet been determined, NO causes an increase

release of glutamate– Finally, LTP requires synthesis of proteins, which is believed to take

place in dendritic spines much like it takes place in and around the cell nucleus

• Second Messenger– Activated by a neurotransmitter (the first messenger)– A chemical that carries a message to initiate a biochemical

process• Examples

– Alter ion flow in a membrane channel– Formation of new ion channels– Production of new proteins

• Learning and Synaptic Plasticity– Mechanisms of Synaptic Plasticity

– CaM-KII:• Type II calcium-calmodulin kinase, an enzyme that

must be activated by calcium; may play a role in the establishment of long-term potentiation.

– Nitric oxide synthase:• An enzyme responsible for the production of nitric

oxide.

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13.4


Role of Synapses in Learning and MemoryLearning at the Synapse

• What neural processes underlie the persistent, long-term changes of learning?– Ca++ enters postsynaptic neuron and activates a

second messenger (e.g., cyclic AMP)– cAMP alters gene expression in nucleus, which

physically alters synapse:• Structural changes in the synapse

– Dendritic spines• Formation or loss of synapses

• Learning and Synaptic Plasticity– Long-term Depression

– Long-term depression:• A long-term decrease in the excitability of a neuron to

a particular synaptic input caused by stimulation of the terminal button while the postsynaptic membrane is hyperpolarized.

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Long-term depression:A long-term decrease in the excitability of a neuron to a particular synaptic input caused by stimulation of the terminal button while the postsynaptic membrane is weakly depolarized or is hyperpolarizedAlso results in a decrease of AMPA receptors found in the cell membrane


Role of Synapses in Learning and MemoryNeurochemistry of LTP

• Long-Term Depression– Another form of synaptic

plasticity– Neuron becomes less active in

response to repeated stimulation

– Involves NMDA receptors – Requires Ca++ entry:

• Decreased responsiveness of AMPA receptors

• Decreased numbers of AMPA receptors

AMPA

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Long term potentiation