Abstract
Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs) contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases.
Highlights
The molecular and cellular mechanisms by which genes and the environment interact to control circuit formation and refinement remain incompletely understood
We showed that presynaptic NMDA receptors (NMDARs) that contain GluN1 and GluN2B are present within the active zone (AZ)
It is clear that NMDARs are found within presynaptic terminals of a variety of neurons, While these receptors have been demonstrated to regulate neurotransmitter release, their developmentallyregulated expression raises the question of what role these receptors play in both normal and abnormal neuronal development
Summary
The molecular and cellular mechanisms by which genes and the environment interact to control circuit formation and refinement remain incompletely understood. NMDAR-dependent regulation at presynaptic terminals that did not have NMDAR-expressing postsynaptic partners (Figure 1B), and at terminals of individual neurons with impaired vesicular glutamate release in an otherwise active network (Figure 1B and [14,15]) These observations led us to hypothesize that presynaptic terminal development is facilitated by the activation of NMDARs in a cell-autonomous manner, without the need for retrograde signaling from postsynaptic partners (Figure 1C). It is not yet clear where the relevant NMDARs are localized, but one intriguing possibility is that glutamate regulates presynaptic development through local activation of presynaptic NMDARs (preNMDARs). We will summarize our current understanding of preNMDARs and discuss their potential role in presynaptic development
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