Molecular and Synaptic Alterations in the Striatum of GluN1-Deficient Mice

N-methyl-D-aspartate receptors (NMDARs) are essential for proper neurodevelopment and cognitive function. NMDAR dysfunction contributes to many neurological disorders, with striatal changes linked to psychosis and cognitive impairment. GluN1 knockdown (GluN1KD) mice have low NMDAR expression, striatal synaptic deficits, and cognitive behavioural abnormalities. How these phenotypes functionally relate to one another is unclear. We studied molecular and synaptic changes in the GluN1KD striatum to understand the molecular underpinnings of GluN1KD behaviours. From a screen of Rho GTPase pathway proteins, which regulate synapses and cognition, Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling proteins were specifically identified. GluN1KD mice at 6 and 12 weeks of age consistently had less Rac1 and its downstream effector Wiskott-Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE-1). These deficits were developmentally aligned with medium spiny neuron (MSN) spine density deficits and previously published behavioural abnormalities. To assess the biological and behavioural significance of these findings, we restored WAVE-1 levels by intercross-breeding GluN1KD mice and WAVE-1 overexpressing (WAVE-Tg) mice. GluN1KD-WAVE-Tg F1 hybrids had improved WAVE-1 levels and spine density at the striatum, as well as better Y-maze and 8-arm radial maze performance. These phenotypic recoveries were not mirrored by WAVE-1 levels in the hippocampus nor by neuronal dendritic spines in cornu ammonis 1. From a broader RNAseq analysis of the GluN1KD striatal transcriptome, both neurodegeneration-related and cell-growth signaling pathways were distinguished as affected by NMDAR knockdown. These transcript changes were greatly sex-dependent, potentially mediated by aberrations of estrogen receptor α signaling. Our data suggest that different molecular changes in male and female GluN1KD mice contribute to similar behavioural abnormalities. Restoring WAVE-1 at the striatum improved some of these phenotypes, pointing to a nuanced relationship between its function, striatal synaptic plasticity, and cognition. Specifically, striatal WAVE-1 and MSN spine density may be important for goal-directed maze exploration in mice.Ph.D