LOSS OF COMPLEXIN 1 IN FAST-SPIKING INTERNEURONS DRIVES MOTOR DEFICITS AND NEURODEGENERATION

Synapses are the fundamental units of information transfer in the nervous system. Although the core neurotransmitter release machinery, including the SNARE complex and its regulators, is conserved across synapses, their precise molecular composition varies and likely underlies distinct functional properties such as synaptic strength, plasticity, and transmission mode. How impaired neurotransmitter release contributes to neurodegeneration remains unclear. Our laboratory previously showed that Complexin 1 (Cplx1), a key SNARE regulator, is particularly important at inhibitory synapses. Constitutive Cplx1 knockout mice recapitulate severe motor and cognitive deficits observed in patients with CPLX1 mutations, implicating cerebellar inhibitory circuits. These mice also show neurodegeneration, but early lethality limits long-term analysis. To overcome this limitation, we generated a novel conditional Cplx1 knockout model selectively targeting PV⁺ neurons, which also expresses the fluorescent reporter TdTomato. This genetic strategy circumvents early lethality and enables cell-type-specific investigation of the functional and molecular mechanisms underlying neurodegeneration, with a particular focus on the cerebellum. Behavioral analyses revealed that selective loss of Cplx1 in PV+ neurons is sufficient to reproduce the motor and cognitive deficits observed in constitutive KO mice. At the functional level, electrophysiological recordings from cerebellar slices demonstrated a pronounced reduction in inhibitory synaptic transmission and significant alterations in short-term plasticity. Furthermore, combined fluorescence and electron microscopy revealed early changes in synaptic protein expression and the presence of ultrastructural abnormalities. Together, these findings highlight the central role of Cplx1 in maintaining inhibitory microcircuit stability and identify it as a potential key factor in the pathogenesis of neurodegenerative motor disorders.