Presynaptic NMDA Receptors

Excerpt

Presynaptic receptors, by virtue of their locations, are ideally suited to influence the efficacy of synaptic transmission by affecting neurotransmitter release [58]. In the nervous system, action potential invasion of presynaptic terminals results in a characteristic series of events: initial Ca²⁺ entry, followed by the activation of presynaptic vesicular release machinery, vesicular fusion, and the release of neurotransmitter into the synaptic cleft [103,105]. The efficacy of synaptic transmission is thus governed by the probability of neurotransmitter release, the amount of transmitter released from the presynaptic terminal, the type and number of postsynaptic neurotransmitter receptors, and their response to the released transmitter.

Short- and long-term activity-dependent modulation of the efficacy of a synapse can proceed via a multitude of signaling mechanisms that impact on either the presynaptic release or the receptors that mediate postsynaptic responses [13,66,102]. Such modulatory mechanisms will be crucial for regulating the flow of information throughout the nervous system and have been implicated in many neural processes including learning and memory, vision, motor control, and neuroprotection.

Modulation of transmitter release at a synapse was first demonstrated in the classical studies of Dudel and Kuffler [30] and Eccles [33] who identified that presynaptic GABA receptors inhibited transmitter release from crustacean motor neuron terminals and vertebrate sensory neuron terminals in the spinal cord, respectively. Since then, the modulation of transmitter release by presynaptic receptors is an accepted signaling pathway, and although the focus of attention initially fell on metabotropic G-protein coupled receptors [52,94], it soon became clear that numerous populations of presynaptic ionotropic receptors are equally important [53,58,67].

One receptor that has not featured prominently as a presynaptic regulator of transmitter release is the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor. It was first proposed to have a presynaptic locus of expression after it was found that exogenously applied NMDA facilitated the release of tritiated neurotransmitter from synaptosomes prepared from noradrenergic terminals in the hippocampus [86], cerebral cortex [37], and from dopaminergic terminals in the striatum [50,56,112]. Because of the nature of the preparations, these early studies failed to identify the exact loci of NMDA receptor (NMDAR) subunit expression.

Further evidence for presynaptic NMDARs came from the pioneering work of Liu and colleagues [62] who identified NR1 subunit immunoreactivity in both the dorsal and ventral horns of the rat spinal cord, specifically on axon terminals and very near the active zone, indicating a direct role in the regulation of transmitter release. Similarly, immunoreactivity for NR1 and NR2 was found on presynaptic boutons in rat cerebellar cortex [82,83] and at mossy fiber CA synapses in monkey hippocampus [98]. These early findings provided the necessary impetus to find a more widespread role for presynaptic NMDARs in the regulation of neuronal signaling in the CNS.

In this chapter, we discuss recent advances in our understanding of presynaptic NMDARs as important modulators of synaptic transmission. We consider the potential sources of glutamate for NMDAR activation; the downstream signaling mechanisms that ensue; and the differing forms of synaptic plasticity mediated by presynaptic NMDARs that undoubtedly help sculpt information processing in the brain.