Hippocampal GluN2A knockdown differentially alters spatial exploration and behavioral performance in male and female rats.

The hippocampus is the brain structure responsible for spatial information processing, map formation, spatially guided behavior, and memory consolidation. Although these processes are often treated as overlapping or even unitary, emerging evidence suggests that they depend on partially dissociable mechanisms. All these processes depend on hippocampal plasticity; more specifically, on NMDA receptor (NMDAR) function and signaling. NMDARs are tetramers containing two obligatory GluN1 subunits and two regulatory subunits whose expression is tightly regulated. Among them, GluN2A, the regulatory subunit mainly expressed in mature structures, is considered a key determinant of synaptic plasticity. Constitutive GluN2A-knockout models have shown impairments in spatial tasks, contextual fear conditioning, and object location memory. However, these models are limited because compensatory mechanisms could be activated during development. To overcome this limitation, we developed an AAV-mediated shRNA knockdown of GluN2A (GluN2A-kd) targeted to the hippocampus in adult Wistar rats, avoiding developmental confounds and enabling the specific assessment of GluN2A function in mature neurons. Our results show that hippocampal GluN2A-kd in adult rats selectively alters spatial exploration and the ability to update spatially guided behavior across tasks, revealing a previously uncharacterized role for GluN2A in the organization of spatial performance rather than in general memory processes. Additionally, we identified a sex-dependent effect of reduced GluN2A expression, suggesting that GluN2A-kd females may exhibit impaired spatial learning or rely on alternative or less efficient spatial strategies to solve the tasks. Together, these findings position GluN2A as a key modulator of the precision and flexibility of spatial behavior required for successful performance in the adult hippocampus.