IMPACT OF MATERNAL ANTI-NEURONAL AUTOANTIBODIES ON HIPPOCAMPAL NETWORK ACTIVITY DURING BRAIN DEVELOPMENT

Maternal anti-neuronal autoantibodies (ABs) have been linked to an increased risk of neurodevelopmental disorders, yet their pathogenic mechanisms remain poorly understood. Here, we investigate how in utero exposure to maternal ABs affects early neural network maturation in the developing hippocampus. Using a passive-transfer mouse model, we show that transplacental ABs targeting the NR1 subunit of NMDA receptors (NR1 ABs) disrupt hippocampal circuit maturation. Ex vivo electrophysiological recordings reveal a marked impairment of GABAergic synaptic input onto CA1 pyramidal cells (PCs). Ca²⁺ imaging combined with computational modeling demonstrates that this synaptic deficit compromises early synchronized network activity in neonatal CA1. In vivo recordings further show that NR1 AB exposure interferes with the emergence of continuous hippocampal activity around eye opening—a critical developmental transition for later cognitive function—by reducing the ability of CA1 PCs to developmentally decouple from local network dynamics. Preliminary data obtained with ABs targeting contactin-associated protein 2 (Caspr2) indicate that these ABs also perturb hippocampal activity patterns in neonates, albeit via distinct network alterations. Together, our findings identify NR1 ABs as drivers of a developing hippocampal circuitopathy and more broadly suggest disrupted activity-dependent circuit refinement as a mechanistic link between maternal autoimmunity and neurodevelopmental dysfunction.