Human Physiology/The Nervous System

11

LTP can be induced either by strong tetanic stimulation of a single pathway to a synapse, or cooperatively via

the weaker stimulation of many. When one pathway into a synapse is stimulated weakly, it produces

insufficient postsynaptic depolarization to induce LTP. In contrast, when weak stimuli are applied to many

pathways that converge on a single patch of postsynaptic membrane, the individual postsynaptic

depolarizations generated may collectively depolarize the postsynaptic cell enough to induce LTP

cooperatively. Synaptic tagging, discussed later, may be a common mechanism underlying associativity and

cooperativity.

LTP is generally divided into three parts that occur sequentially: Short-term potentiation, early LTP (E-LTP) and late

LTP (L-LTP). Short-term potentiation isn't well understood and will not be discussed.

E-LTP and L-LTP phases of LTP are each characterized by a series of three events: induction, maintenance and

expression. Induction happens when a short-lived signal triggers that phase to begin. Maintenance corresponds to the

persistent biochemical changes that occur in response to the induction of that phase. Expression entails the

long-lasting cellular changes that result from activation of the maintenance signal.

Each phase of LTP has a set of mediator molecules that dictate the events of that phase. These molecules include

protein receptors, enzymes, and signaling molecules that allow progression from one phase to the next. In addition to

mediators, there are modulator molecules that interact with mediators to fine tune the LTP. Modulators are a bit

beyond the scope of this introductory book, and won't be discussed here.

Early Phase

Induction

E-LTP induction begins when the calcium inside the postsynaptic cell exceeds a threshold. In many types of LTP,

the flow of calcium into the cell requires the NMDA receptor, which is why these types of LTP are considered

NMDA receptor-dependent.

When a stimulus is applied to the presynaptic neuron, it releases a neurotransmitter, typically glutamate, onto the

postsynaptic cell membrane where it binds to AMPA receptors, or AMPARs. This causes an influx of sodium ions

into the postsynaptic cell, this short lived depolarization is called the excitatory postsynaptic potential (EPSP) and

makes it easier for the neuron to fire an action potential.

A single stimulus doesn't cause a big enough depolarization to trigger an E-LTP, instead it relies on EPSP

summation. If EPSPs are reaching the cell before the others decay, they will add up. When the depolarization reaches

a critical level, NMDA receptors lose the magnesium molecule they were originally plugged with and let calcium in.

The rapid rise in calcium within the postsynaptic neuron trigger the short lasting activation of several enzymes that

mediate E-LTP induction. Of particular importance are some protein kinase enzymes, including CaMKII and PKC.

To a lesser extent, PKA and MAPK activation also contribute.

Maintenance

During the maintenance stage of E-LTP, CaMKII and PKC lose their dependence on calcium and become

autonomously active. They then carry out phosphorylation that underlies E-LTP expression.

Expression

CaMKII and PKC phosphorylate existing AMPA receptors to increase their activity, and mediate the insertion of

additional AMPA receptors onto the postsynaptic cell membrane. This is achieved by having a pool of nonsynaptic

AMPA receptors adjacent to the postsynaptic membrane. When the appropriate stimulus arrives, the nonsynaptic

AMPA receptors are brought into the postsynaptic membrane under the influence of protein kinases.

AMPA receptors are one of the most common type of receptors in the brain. Their effect is excitatory. By adding

more AMPA receptors, and increasing their activity, future stimuli will generate larger postsynaptic responses.