Anti-N-methyl-d-aspartate-receptor (NMDAR) encephalitis is the most common type of autoimmune encephalitis that frequently affects young and middle-aged adults (Papi et al., 2024; Venkatesan and Adatia, 2017). Although immunotherapy is effective in ameliorating acute psychiatric and neurological symptoms, over 80% of survivors experience persistent cognitive impairments, including memory loss, attentional deficits, and executive dysfunction, which profoundly reduce daily functioning and quality of life (Brenner et al., 2024; Chen et al., 2022; Heine et al., 2021). Nonetheless, the precise nature of these cognitive deficits, especially executive dysfunction is poorly understood. Cognitive flexibility, the ability to adapt behavior in response to changing environmental contingencies, is a key component of executive function (Chehrazi et al., 2023). Despite its clinical importance, this domain has been largely overlooked in preclinical models of NMDAR encephalitis. Most existing studies have focused on memory deficits and hippocampal dysfunction (Hechler et al., 2024; Kersten et al., 2019; Malviya et al., 2017; Planaguma et al., 2015; Taraschenko et al., 2024), leaving a critical gap in our understanding of how NMDAR autoantibodies impact other brain regions crucial to cognitive function, particularly the medial prefrontal cortex (mPFC), which plays a central role in executive control and behavioral flexibility (Lupien-Meilleur et al., 2021; Yan and Rein, 2022).

NMDAR encephalitis is mediated by highly specific autoantibodies targeting the amino-terminal domain of the GluN1 subunit. These antibodies bind to cell-surface NMDARs and induce their internalization, thereby disrupting synaptic receptor density and impairing synaptic plasticity (Dalmau and Graus, 2018; Seery et al., 2022). Passive transfer of anti-NMDAR antibodies or active immunization with NMDAR antigen in animal models have replicated aspects of cognitive impairments, especially the memory deficits, through these mechanisms (Malviya et al., 2017; Pan et al., 2019; Papi et al., 2024; Planaguma et al., 2015; Yang et al., 2024). However, it remains unclear whether and how these antibodies affect prefrontal circuits that mediate higher-order cognitive processes such as cognitive flexibility.

Prefrontal disinhibition, characterized by reduced GABAergic signaling within the mPFC, has been implicated in cognitive inflexibility across a range of neuropsychiatric disorders, including schizophrenia, autism spectrum disorder, and epileptic encephalopathies (Lupien-Meilleur et al., 2021; Nakazawa and Sapkota, 2020; Shao et al., 2023). In vitro studies using cultured cortical neurons have demonstrated that anti-NMDAR IgG preferentially disrupts inhibitory interneurons over excitatory neurons (Andrzejak et al., 2022). Furthermore, a recent study using 7-day microinjection of anti-NMDAR IgG into the mPFC revealed pathological changes in parvalbumin (PV)-expressing interneurons, supporting the hypothesis that local disinhibition within mPFC contributes to cognitive deficits associated with NMDAR encephalitis (Feng et al., 2025). However, these localized models may not fully capture the broader or more persistent effects of antibody exposure observed in clinical NMDAR encephalitis.

To address this, we established a murine model of NMDAR encephalitis using a 14-day continuous intracerebroventricular (ICV) infusion of anti-GluN1 IgG, enabling sustained and brain-wide exposure that more closely mimics the clinical course of NMDAR encephalitis. Using this model, we aimed to determine whether prolonged exposure to NMDAR antibodies induces cognitive rigidity and to explore the associated synaptic alterations in the mPFC. By combining behavioral assessments with molecular and electrophysiological analyses, this study characterizes prefrontal GABAergic dysfunction and local disinhibition associated with persistent cognitive inflexibility in a murine model of NMDAR encephalitis. These findings shed light on potential circuit-level correlates of enduring executive dysfunction and suggest that impaired cognitive flexibility may serve as a clinically relevant readout of prefrontal cortical involvement in antibody-mediated encephalitis.