Reduced astrocytic Homer1a expression mediates mPFC excitatory synaptic dysfunction and neurodevelopmental deficits after maternal immune activation

Abstract Prenatal maternal immune activation (MIA) during pregnancy is a prominent environmental contributor to neurodevelopmental disorders and psychiatric conditions in offspring, but the precise brain-region- and cell-type-specific mechanisms remain unclear. Using a lipopolysaccharide (LPS)-induced MIA mouse model, we show that prenatal inflammatory challenge causes persistent anxiety-like behaviors and cognitive impairments in male offspring, along with sustained neuroinflammation, astrocyte hyperactivation, and selective perturbation of excitatory (but not inhibitory) tripartite synapses in the medial prefrontal cortex (mPFC). Bulk RNA sequencing (RNA-seq), together with immunofluorescence data, reveals preferential downregulation of astrocytic Homer1a in mPFC, without global dysregulation of other immediate early genes (IEGs). Astrocyte-targeted Homer1a overexpression in the mPFC rescues these MIA-induced behavioral, inflammatory and synaptic abnormalities. Mechanistically, reduced astrocytic Homer1a expression increases intracellular Ca²⁺ levels, activates Calcineurin (CaN)/nuclear factor of activated T cells c4 (NFATc4) signaling, and downregulates glutamate transporter 1 (GLT1). This cascade disrupts astrocyte-dependent glutamate and synaptic homeostasis, thereby impairing neuronal structure and contributing to long-term neurobehavioral deficits. Our findings define an astrocyte‑specific, excitatory synapse‑selective pathogenic cascade mediated by the Homer1a–Ca²⁺/CaN/NFATc4/GLT1 axis in MIA‑related neurodevelopmental deficits. These findings support astrocytic Homer1a as a novel mediator linking prenatal inflammation to long-term neurobehavioral deficits in male offspring.