NMDA receptors and callosal circuitry: development and molecular mechanisms

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The corpus callosum (CC) is the largest commissural projection connecting homotopic regions of the hemispheres in mammals. The connectivity of the CC is essential for coordinated motor-sensory function and for many higher cognitive processes. The CC is also a valuable model system for understanding circuit development as well as possible mechanisms underlying disorders of circuit form and function such as psychosis, autism and epilepsy. We have become interested in the role of NMDA receptors (the chief excitatory neurotransmitter receptor in the cortex) in cortical circuit development and maintenance. NMDAR are located at synapses and are known to be critical for circuit plasticity in many contexts and are also known to interact with guidance cues, such as the Eph Receptors (EphR) during development. Also, dysfunction of NMDAR caused by anti-NMDAR antibodies has achieved recent prominence as a model for psychosis. Patients with anti- NMDAR antibody encephalitis present with psychosis, abnormal movements and seizures. The clinical features of this syndrome, including the subacute onset and slow recovery after treatment suggest functional disruption at the level of circuit integrity rather than simple pharmacologic antagonism. We are examining the role of NMDAR in development of somatosensory projections of the CC. We find that Emx1cre/+; NR1fl/fl mice, lacking NMDAR specifically in the cortex after E10.5, have callosal defects in primary somatosensory cortex (S1) and that this is associated with alterations in EphB2 expression. Our analysis shows defects of both initial innervation and subsequent refinement. Also, intraventricular injections of anti-NMDAR antibodies, similar to pathogenic patient antibodies, cause similar defects in the innervation of S1. We propose, that the function of the NMDAR is necessary for homotopic callosal projections, that NMDAR have specific roles in shaping the callosal circuitry by affecting axon pathfinding and/or axon pruning in the developing cortex and that continued NMDAR function is critical for morphologic maintenance of the circuit. The aims below will test these propositions and examine potential molecular mechanisms. Aim1: Determine the anatomic and temporal roles of NMDAR in callosal development. Aim2: Characterize the role of NR2A and NR2B subunits in callosal development. Aim3: Identify interactions between NMDAR and EphrinB/EphB signaling in callosal development.