In utero exposure to NMDA receptor autoantibodies disrupts hippocampal circuit maturation

In utero exposure to NMDA receptor autoantibodies disrupts hippocampal circuit maturation

Myrtill Majoros, Chuanqiang Zhang, Vahid Rahmati, Jürgen Graf, Manfred Heckmann, Christian Geis, Jakob Kreye, Angela M. Kaindl, Harald Prüss, Knut Holthoff, Knut Kirmse

Majoros et al., 2026, Cell Reports 45, 117022 

Maternal anti-neuronal autoantibodies (ABs) have been linked to abnormal brain maturation and may increase the risk of neurodevelopmental disorders, yet their pathogenetic mechanisms remain elusive. Here, we show that in utero exposure to ABs targeting the NR1 subunit of N-methyl-D-aspartate (NMDA) receptors (NR1 ABs) disrupts hippocampal circuit maturation in mice. Using a passive-transfer model, we find that transplacental NR1 ABs impair GABAergic transmission in CA1 pyramidal cells (PCs) ex vivo. Ca²⁺ imaging and computational modeling reveal that this deficit compromises early synchronized network activity in neonatal CA1. In vivo, NR1 ABs hinder the emergence of continuous activity around eye opening—a critical milestone for later cognitive function—by reducing the ability of CA1 PCs to developmentally decouple from local network dynamics. Our findings implicate NR1 ABs as drivers of a developing hippocampal circuitopathy and highlight disrupted activity-dependent circuit refinement as a mechanistic link between maternal autoimmunity and neurodevelopmental dysfunction.

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