Role of the NMDA receptor subunit, NR3A, in glutamatergic synapse development

Proper functioning of neuronal networks relies on the refinement of immature synaptic contacts, although many aspects of this process are poorly understood. NMDA-type glutamate receptors (NMDARs) are crucial mediators of brain development and function, especially excitatory synapse development. Accumulating evidence suggests that the NR3A subtype of NMDARs has an unappreciated and particularly important role during early postnatal development. These developmentally regulated receptor subunits serve a prominent role in CNS development soon after birth, and their role is likely less important prenatally and in adulthood. Inclusion of the nonconventional NR3A subunit in NMDARs may serve to alter cortical microcircuitry in the brain anatomically, through reduced numbers of dendritic spines, and functionally, through weakened synaptic connections due to decreased glutamatergic neurotransmission and calcium influx through NMDARs. In this dissertation, using molecular and biochemical techniques in human and mouse model systems, I explored (1) how developmental changes in the complement of glutamate receptors, specifically NR3A subunits, enable synapses to mature or to be eliminated in the mouse forebrain, and (2) whether an increase in NR3A subunit expression could provide an endogenous basis for the NMDAR hypofunction observed in schizophrenia. Because the profound effects that NR3A is likely to have on synapse development have not been fully considered, my research addresses this gap in our knowledge. Dissecting the contributions of specific NMDAR subunits to synapse development will increase our understanding of the maturation of forebrain circuitry and its effects on learning and memory processes, as well as guide therapeutic strategies for treating pathologies associated with NMDAR dysfunction, such as schizophrenia