Neuroscience/Objectives/Lecture 37

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LTP and the hippocampus

Draw the elements of the hippocampus, including the entorhinal cortex, subiculum, CA subfields, and dentate gyrus.

Identify the major afferent and efferent pathways of the hippocampus with the neocortex and subcortical structures.

Describe the neuronal connections within the hippocampus, including the mossy fiber pathway and the Schaffer collateral pathway.

Describe several neurological conditions that result in damage to the hippocampus.

Anoxia is particularly damaging to the hippocampus for unknown reasons.

Explain long-term potentiation on a cellular level.

The NMDA receptor detects simultaneous pre- and postsynaptic activity, causing the influx of Ca²⁺ into the postsynaptic cell. Ca²⁺ binds calmodulin, initiating a number of postsynaptic signaling cascades the results in the expression of LTP. One mechanism of expression is the insertion of AMPA receptors into the postsynaptic membrane, allowing subsequent releases of presynaptic glutamate to better stimulate the postsynaptic cell. Another mechanism includes the expression of plasticity-related proteins, including those related to the growth and remodeling of dendritic spines. Additionally, the induction of LTP may bring about the synthesis of a retrograde messenger (though most likely not nitric oxide or arachidonic acid) that enhances the release of presynaptic neurotransmitters on subsequent stimuli. Together, these enhance the strength of the synapse, resulting in a potentiation of the response to subsequent stimuli.

Explain the role of NMDA and AMPA receptors in LTP.

In most forms of associative LTP, NMDA receptors play the role of coincidence detector, becoming active only when both pre- and postsynaptic cells are depolarized. The ability of NMDARs to detect simultaneous pre- and postsynaptic activity rests in the NMDAR being both ligand- and volgate-gated. The ligand gate is opened only when the presynaptic cell is active and therefore releasing neurotransmitter (i.e. glutamate); the voltage gate is opened only when the postsynaptic cell is active and therefore depolarized. Thus the NMDAR is open only when both pre- and postsynaptic cells are active; hence, NMDARs detect the coincident activation of pre- and postsynaptic cells. They provide a Ca²⁺ signal that triggers the induction of long-term potentiation.

This Ca²⁺ signal triggers downstream events in the postsynaptic cell that ultimately strengthen the synapse between pre- and postsynaptic cells. The primary mechanism by which the synapse is strengthened is through the insertion of AMPA receptors into the postsynaptic membrane. AMPARs are ligand-gated only, and so will become active on subsequent release of presynaptic glutamate (without needing the postsynaptic cell to be simultaneously depolarized). Thus inserting AMPARs increases the efficiency with which the presynaptic cell can activate the postsynaptic cell, causing the postsynaptic response to be enhanced (or potentiated) with subsequent applications of a stimulus of the same strength. This is long-term potentiation.

Describe silent synapses and what happens to them during LTP.

A silent synapse is one whose postsynaptic membrane has NMDA receptors but no AMPA receptors. Since NMDARs are voltage- and ligand-gated, glutamate released by the presynaptic terminal is not sufficient to open NMDARs. This contrasts active synapses containing AMPARs, in which the presynaptic release of glutamate is sufficient to open AMPARs and elicit an EPSP. The voltage-dependence of NMDARs is what makes silent synapses functionally silent under normal circumstances.

Silent synapses can be made active by opening these NMDARs. This is done by simultaneously opening the NMDAR's voltage and ligand gates. Strong depolarization of the postsynaptic cell will remove the magnesium blockade and open the NMDAR's voltage gate, while the simultaneous binding of glutamate to the NMDAR opens the voltage gate. The end result is that Ca²⁺ enters the postsynaptic cell and activates a number of kinases (eg, CaM kinase II), resulting in AMPA receptors being inserted into the postsynaptic membrane. This converts the silent synapse into an active one, since AMPA receptors are not voltage-gated and open in response to glutamate binding.