RT Journal Article SR Electronic T1 Deficits in integrative NMDA receptors caused by Grin1 disruption can be rescued in adulthood JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.11.22.517556 DO 10.1101/2022.11.22.517556 A1 S. Venkatesan A1 M.A. Binko A1 C.A. Mielnik A1 A.J. Ramsey A1 E.K. Lambe YR 2022 UL http://biorxiv.org/content/early/2022/11/23/2022.11.22.517556.abstract AB Glutamatergic NMDA receptors (NMDAR) are critical for cognitive function, and their reduced expression leads to intellectual disability. Since subpopulations of NMDARs exist in distinct subcellular environments, their functioning may be unevenly vulnerable to genetic disruption. Here, we investigate synaptic and extrasynaptic NMDARs on the major output neurons of the prefrontal cortex in mice deficient for the obligate NMDAR subunit encoded by Grin1 and wild-type littermates. With whole-cell recording in brain slices, we find that single, low-intensity stimuli elicit surprisingly-similar glutamatergic synaptic currents in both genotypes. By contrast, clear genotype differences emerge with manipulations that recruit extrasynaptic NMDARs, including stronger, repetitive, or pharmacological stimulation. These results reveal a disproportionate functional deficit of extrasynaptic NMDARs compared to their synaptic counterparts. To probe the repercussions of this deficit, we examine an NMDAR-dependent phenomenon considered a building block of cognitive integration, basal dendrite plateau potentials. Since we find this phenomenon is readily evoked in wild-type but not in Grin1-deficient mice, we ask whether plateau potentials can be restored by an adult intervention to increase Grin1 expression. This genetic manipulation, previously shown to restore cognitive performance in adulthood, successfully rescues electrically-evoked basal dendrite plateau potentials after a lifetime of NMDAR compromise. Taken together, our work demonstrates NMDAR subpopulations are not uniformly vulnerable to the genetic disruption of their obligate subunit. Furthermore, the window for functional rescue of the more-sensitive integrative NMDARs remains open into adulthood.Competing Interest StatementThe authors have declared no competing interest.