Sex-Dependent Effects of Glutamatergic Disruption on Dopaminergic Neuron Subtype Vulnerable in Parkinson’s Disease

We investigated the role of glutamatergic input by conditionally deleting Grin1, encoding a critical NMDA receptor subunit, in ALDH1A1+ neurons. Grin1 conditional knockout mice showed normal locomotion and motor learning, but females exhibited increased operant reward acquisition along with excessive feeding and weight gain after food restriction.

To determine regional contributions in female mice, we selectively knocked down Grin1 in ALDH1A1+ neurons of the ventral tegmental area (VTA) or substantia nigra pars compacta. VTA-specific knockdown in females reproduced the post-restriction feeding and weight gain phenotype. Bulk whole-brain mRNA sequencing revealed significant gene expression changes based on sex primarily in Grin1 conditional knockout mice following food restriction.