Coq

Baseline i-r

C1. Control

Glutamate Na+

Non-NMDA-receptor

Glutamate

NMDA receptor

Glutamate Na+

C2. Induction (during tetanus)

Glutamate

Non-NMDA receptor

Glutamate

NMDA receptor

FIGURE 6 Long-term potentiation (LTP). (A) Experimental arrangements for analyzing LTP in the CNS. An intracellular recording is made from a postsynaptic cell (in this case, a pyramidal cell in the CA1 region of the hippocampus), and electric shocks are delivered to an afferent pathway (the Schaeffer collateral pathway) that projects to the postsynaptic neuron. (B) Stimulus protocol and results: (B1) Single weak electric shocks are repeatedly delivered to the afferent pathway. After obtaining several stable baseline responses, a brief high-frequency tetanus is delivered. After the tetanus, the low frequency test stimulation is resumed. (B2) EPSPs are normalized to their control (pretetanus level). The tetanus produces short-term enhancement (post-tetanic potentiation, or PTP) followed by an enduring enhancement (LTP) that persists for at least 2 hours. (C) Mechanisms for the induction of LTP (at the Schaeffer collateral-CA1 pyramidal cell synapse): (C1) The spines of the postsynaptic cell have both NMDA and non-NMDA glutamate receptors. Glutamate released by test stimuli binds to and activates the non-NMDA receptors. Glutamate released by test stimuli also binds to NMDA receptors, but no ions flow through the NMDA channels because they are blocked by Mg2+. (C2) The tetanus produces a large postsynaptic depolarization that displaces the Mg2+ from the pore of the NMDA channel. Ca2+ can now flow into the spine through the NMDA channel and induce a cascade of biochemical reactions (including activation of Ca2+-dependent protein kinases, or PKs) that lead to a change in synaptic efficacy.

many hours. This enduring enhancement is referred to as LTP.

Although LTP of the form illustrated in Fig. 6B2 has been observed at a number of synapses, the underlying mechanisms for these different examples of LTP can differ. The following discussion will focus on the mechanisms for LTP at a particular synapse (the Schaeffer collateral-CAl pyramidal cell synapse) in the hippocampus. The mechanism at this synapse takes advantage of some of the unique properties of the N-methyl-D-aspartate (NMDA) receptor described in Chapter 6.

The Schaeffer collateral axons make synaptic contacts with the pyramidal cells on specialized dendritic structures called spines. The spines have both NMDA and non-NMDA glutamate receptors (Fig. 6C). Test stimuli lead to the release of glutamate from the afferent terminal, which diffuses across the synaptic cleft and binds with both types of receptors. Binding to the non-NMDA receptor leads to an increase in the permeability to Na+ and K+ and a subsequent small EPSP. Glutamate also binds to the NMDA receptor but because of the block by Mg2+ no permeability changes occur. In contrast, the tetanus produces a large depolarization of the spine because of both temporal summation of the effects of the individual EPSPs produced by the non-NMDA receptors at that spine and spatial summation of the effects of EPSPs produced at spines contacted by the other afferent fibers that are conjointly activated by the nerve shock. The resultant large depolarization of the spine displaces Mg2+ from the NMDA receptor, which allows Ca2+ influx to occur. As described later, the Ca2 + influx through the NMDA receptor is essential for the induction of LTP. The rationale for stimulating multiple afferents (Fig. 6A) should now be clear. In order to remove the Mg2+ block of the NMDA channel, depolarization from multiple afferents is necessary.

The Ca2+ influx through the NMDA channel activates one or more Ca2+-dependent protein kinases (PKs) (Fig. 6C2), and the phosphorylation of substrate proteins leads to an enduring change in synaptic efficacy. The mechanisms for the induction steps subsequent to the activation of kinases are not fully understood. One possibility is a postsynaptic modification, such as an increase in the number of non-NMDA receptors that are available to bind with transmitter released by the post-tetanus test stimuli. Alternatively, there may be a retrograde messenger released by the postsynaptic cell to directly affect aspects of the release mechanism in the presynaptic neuron. Analyses to distinguish between these possibilities have yielded conflicting results. It is likely that LTP at the Schaeffer collateral-CAl pyramidal synapse involves modifications of both pre- and postsynaptic processes.

In principle, LTP at this synapse could be induced by activation of a single afferent fiber, but the depolarization produced by a single presynaptic neuron (even with a tetanus) is insufficient to relieve the Mg2+ block of the postsynaptic NMDA channel. Thus, other neurons must be activated as well. For example, a tetanus to one afferent pathway in conjunction with a weak test stimulus to a separate pathway would lead to an enhancement of the test pathway even though the test pathway was not tetanized. In this case, the tetanized pathway provides the depolarization to relieve the Mg2+ block at the synapse of the test pathway.

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