PARVALBUMIN-SPECIFIC LOSS OF COMPLEXIN I DISRUPTS INHIBITORY SYNAPTIC FUNCTION AND HIPPOCAMPAL OUTPUT

The presynaptic SNARE complex regulator Complexin 1 (Cplx1) stabilizes primed synaptic vesicles at the active zone and promotes their fusion upon action potential arrival. Although its synaptic role has been extensively characterized in vitro and at selected synapses, the broader physiological impact of Cplx1 on circuit function across brain regions remains poorly understood. Clinically, missense and loss-of-function mutations in CPLX1 cause intellectual disability and epileptic encephalopathies, while constitutive Cplx1 knockout (KO) mice recapitulate key aspects of the human phenotype, suggesting that disrupted excitation/inhibition (E/I) balance contributes to disease pathology. Parvalbumin-expressing (PV+) interneurons are fast-spiking inhibitory neurons essential for controlling excitatory activity within local circuits. We hypothesized that these neurons are particularly vulnerable to Cplx1 loss and generated a conditional Cplx1 KO selectively targeting PV+ cells (PV-cCplx1KO). We focused on the hippocampus due to its role in declarative memory and high epileptogenic potential. Structural analyses using confocal and electron microscopy revealed alterations in synaptic protein expression and ultrastructure in PV-cCplx1KO hippocampi. Electrophysiological recordings uncovered pronounced functional deficits, including reduced inhibitory synaptic strength and altered short-term plasticity of inhibitory inputs onto CA3 pyramidal neurons. Consequently, feedforward inhibition was impaired, leading to abnormal CA3 output characterized by reduced firing precision and altered firing probability. Consistent with these circuit defects, behavioral testing revealed significant episodic memory impairments. Together, these findings demonstrate a critical role for Cplx1 in maintaining hippocampal E/I balance through fast inhibitory transmission and identify PV+ interneuron dysfunction as a key contributor to epileptic encephalopathy and cognitive deficits in Cplx1-associated disorders.