Selective Molecular Modification to Calcium Conductance Domains of NMDA Receptor GluN2 Subunits Regulates Maturation of Hippocampal Behavior




Sanders, Erin Morgan

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The hippocampus is essential for formation and retrieval of autobiographical memories, deliberative decision-making, and spatial navigation. One emerging model to better understand detailed relationships between hippocampal activity and complex cognitive abilities is to investigate neural modifications during the postnatal period when hippocampal-dependent behaviors are first displayed. Electrophysiological and behavioral indices of contextual encoding in rodents are present at roughly seventeen days of age, while spatial navigation is delayed until the end of the third postnatal week. Given younger animals seem capable of encoding space, why does spatial navigation require nearly a week more of development to emerge? Modifications in glutamate receptors occur in parallel with the emergence of spatial navigation. Prominently, N- methyl-D-aspartate receptors (NMDARs) containing GluN2B are replaced by NMDARs with GluN2A subunits during the third postnatal week. This subunit switch produces alterations in calcium conductance profiles and intracellular protein-protein signaling of NMDARs, both of which are implicated in activity-dependent synaptic plasticity and likely regulate the developmental emergence of spatial navigation. We engineered transgenic mice to express chimeric GluN2 subunits to isolate amino acid domains regulating calcium conduction from those dictating intracellular protein-protein signaling. We documented expression of chimeric GluN2 subunits and applied behavioral assays at three postnatal weeks of age. Results indicate a primary role for alterations in calcium conductance in the emergence of spatial navigation. These findings define molecular and physiological factors that are critical for spatial navigation and provide basic information about neural and cognitive development that also help to understand neurodevelopmental disorders.



Glutamatergic synapses, Hippocampal behaviors, Hippocampal maturation, N-Methyl-D-Aspartate Receptor, Spatial learning