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

Aldehyde dehydrogenase 1A1-positive (ALDH1A1+) dopaminergic neurons are selectively vulnerable in Parkinson’s disease (PD), yet how their activity is shaped by presynaptic inputs is unclear. 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. Many of the differentially expressed genes were associated with energy production, metabolic responses, and glial function. These findings reveal a sex-specific role for NMDA receptor–mediated glutamatergic input to ALDH1A1+ VTA neurons in regulating feeding behavior, providing mechanistic insight into how dysfunction of this vulnerable subpopulation may contribute to PD-related non-motor symptoms.