Experience-dependent regulation of presynaptic NMDA receptors (preNMDARs) and their role in neurotransmission and synaptic plasticity

Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDA-type glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Though NMDARs are classically thought to be postsynaptic, recent evidence demonstrates that presynaptic NMDARs (preNMDARs) also exist and have critical roles in synapse function and plasticity. One of the most fascinating areas of research for postsynaptic NMDARs is how they are modified with development and experience and how their changing roles in synaptic transmission and synaptic plasticity change with sensory driven activity. Only a small number of studies have suggested that preNMDARs are modified with experience and a mechanism for this change has been speculative at best. Also highly speculative is the question of how preNMDARs are able to function tonically. In this dissertation I hope to satisfy both queries with one solution. I will attempt to explain how preNMDARs are tonically active and how this can explain their developmental and possibly experience-dependent modifications. Chapter 1 reviews the current knowledge of the role of preNMDARs in synaptic transmission and plasticity, in the neocortex, and a discussion of the prevalence, function, and development of these receptors. Chapter 2 provides the first evidence of developmental control of preNMDAR expression, function, and role in synaptic plasticity. Chapter 3 answers the most perplexing question that plagues the study of preNMDARs "how do they overcome their Mg2+ block to be tonically active?" Here, evidence is presented that preNMDARs contain the novel subunit NR3A which is substantially less Mg2+ sensitive allowing preNMDARs to be tonically active. Thus, the developmental loss of NR3A would cause the preNMDAR to loose its tonic activity though not its ability to enhance spontaneous release in Mg2+ free solution. Chapter 4 suggests that preNMDARs may not be subject only to developmental control but may also be modified by experience. Chapter 5 explores how altered visual experience modifies preNMDARs at different points in development. Chapter 6 discusses how these findings will contribute to the study of preNMDARs, clinical outcomes of this research, and possible future directions

Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity

Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDA-type glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Classically, NMDARs were thought to be exclusively postsynaptic. However, substantial evidence in the last 10 years demonstrates that NMDARs also exist presynaptically, and that presynaptic NMDA receptors (preNMDARs) modulate synapse function and have critical roles in plasticity at many synapses. Here we review current knowledge of the role of preNMDARs in synaptic transmission and plasticity, focusing on the neocortex. We discuss the prevalence, function, and development of these receptors, and their potential modification by experience and in brain pathology

Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses

Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses

Nr3a-containing NMDA receptors promote neurotransmitter release and spike timing-dependent plasticity

Recent evidence suggests that presynaptic-acting NMDA receptors (preNMDARs) are important for neocortical synaptic transmission and plasticity. We found that unique properties of the Nr3a subunit enable preNMDARs to enhance spontaneous and evoked glutamate release and that Nr3a is required for spike timing–dependent long-term depression in the juvenile mouse visual cortex. In the mature cortex, Nr2b-containing preNMDARs enhanced neurotransmission in the absence of magnesium, indicating that presynaptic NMDARs may function under depolarizing conditions throughout life. Our findings indicate that Nr3a relieves preNMDARs from the dual-activation requirement of ligand-binding and depolarization; the developmental removal of Nr3a limits preNMDAR functionality by restoring this associative property

Synapse-specific control of experience-dependent plasticity by presynaptic NMDA receptors.

Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neurotransmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses