The role of the NMDA receptor subunit GluN2A in synaptic and structural plasticity in the mouse dentate gyrus

The N-methyl-D-aspartate (NMDA) receptor has been closely associated with learning and memory process in the hippocampus. The different subunits that comprise the NMDA receptor convey unique biophysical properties to these receptors. The GluN2A and GluN2B subunits (formerly NR2A and NR2B, respectively) are particularly abundant in the hippocampus, however their role in synaptic, structural and behaviour plasticity remains unclear. In this thesis, we use mice lacking GluN2A subunit expression to fully examine the role of the GluN2A subunit in the first region of the hippocampus, the dentate gyrus (DG). We reveal a significant deficit in the ratio of NMDA to AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors in mature dentate granule cells (DGCs). At a synaptic level, both long-term potentiation (LTP) and long-term depression (LTD) are significantly impaired in the DG, but not the neighboring CA1 region of GluN2A-/- mice. In addition to this decrease in bidirectional synaptic plasticity, GluN2A-/- animals show impairments in spatial pattern separation tasks that have been reported to be DG-specific. In contrast, GluN2A-/- mice showed no deficits in temporal pattern separation, a process associated with CA1 functioning. At a structural level, quantitative immunohistochemistry revealed that GluN2A deletion did not alter the levels of cell proliferation and neuronal differentiation in the adult DG. However, there were significant alterations in the morphology of late immature DGCs. Specifically, GluN2A deletion significantly decreased total dendritic length and dendritic complexity in late immature DGCs. Furthermore, late immature GluN2A-/- DGCs also showed a localized increase in spine density in the middle molecular layer, a region innervated by the medial perforant path. Interestingly, alterations in dendritic morphology and spine density were no longer seen in mature cells. Our data indicates that the GluN2A subunit plays a critical role in bidirectional synaptic plasticity, neuronal morphology and spatial pattern separation in the DG.Medicine, Faculty ofGraduat