Anti-NMDAR antibody exposure induces cognitive inflexibility and prefrontal GABAergic dysregulation in mice.

Anti-N-methyl-d-aspartate-receptor (NMDAR) encephalitis often leads to long-term cognitive impairments, including deficits in executive function, even after acute symptoms resolution, but the underlying mechanisms remain unclear. To explore this, a murine model was established via 14-day intracerebroventricular (ICV) infusion of anti-GluN1 IgG. Mice exhibited deficits in cognitive flexibility and short-term recognition memory, as evidenced by impaired performance in reversal learning and in the novel object recognition test, while spatial learning and anxiety-related behaviors were spared. Molecular analyses revealed decreased expression of GluN1 and GABAergic markers (GAD67, vGat) in the medial prefrontal cortex (mPFC). This disinhibition likely underlies the increased recruitment of excitatory neurons in the mPFC as suggested by the c-Fos expression, which may contribute to the cognitive rigidity in anti-GluN1 IgG-infused mice. Moreover, ex vivo electrophysiological recordings from mPFC pyramidal neurons showed increased sensitivity of spike generation together with diminished inhibitory synaptic input in anti-GluN1 IgG-infused mice. Together, these findings point to mPFC dysfunction, possibly involving GABAergic disruption and local disinhibition, as a candidate mechanism contributing to persistent cognitive rigidity in NMDAR antibody-associated encephalitis.