Sustained inhibitory dysfunction in complement component C1qa-deficient mice underlies epilepsy and comorbidities.

Abstract

Neuronal networks undergo critical refinement throughout development and adulthood to maintain proper brain function. Dysregulation of complement component C1qa-including both up- and downregulation-has been linked to circuit dysfunction and neurological disorders such as epilepsy, primarily through effects on excitatory synapses. However, the impact of C1qa downregulation on inhibitory circuits remains poorly understood. We show that germline deletion of C1qa disrupts layer 6 somatostatin (SST)-expressing interneurons in the somatosensory cortex, which we propose underlies enhanced excitatory synaptic transmission, electrographic spike-and-wave discharges, anxiety-like behavior, and impaired sensory-driven behavior. Transplantation of medial ganglionic eminence (MGE)-derived interneuron precursors rescued behavioral deficits but did not abolish the seizure phenotype, underscoring the critical role of C1qa in maintaining inhibitory network integrity-while also suggesting that additional mechanisms beyond interneuron dysfunction contribute to the pathophysiology of absence seizures.