AUTISM-LIKE BEHAVIOR INDUCED BY CONDITIONAL ABLATION OF THE BASSOON GENE IN GABAERGIC INTERNEURONS

Synapses are critical for brain function. Dysfunctions of these interneuronal connections, such as imbalances between excitatory and inhibitory transmissions, can cause neurodevelopmental brain disorders, including autism spectrum disorders (ASD). Bassoon, a presynaptic scaffolding protein, is present at both glutamatergic and GABAergic brain synapses. It is important for the structural and functional organization of the active zone of neurotransmitter release, regulation of presynaptic proteastasis and synapto-nuclear communication. Here, using cKO mice lacking Bassoon in inhibitory forebrain interneurons, we explore the role of Bassoon in GABAergic synapses. These cKO mice show reduced synaptic vesicle numbers and reduced synaptic efficacy of affected inhibitory synapses, as well as diminished GABAergic inhibition in hippocampal pyramidal neurons. Bsn mutants further displayed a reconfiguration of the hippocampal synaptic network in vivo, as evidenced by subfield-specific changes in inhibitory synaptic markers and reduced numbers of parvalbumin interneurons, culminating in disturbances of hippocampal network activity patterns and profound mitochondrial and metabolic dysregulation. Importantly, the mutant mice developed behavioral abnormalities reminiscent of ASD, including widespread social behavioral deficits and novelty-induced hyperarousal with altered motor behavior, increased anxiety, and epileptiform activity. Bsn conditional knock-out mice thus provide strong evidence for a causal role of GABAergic synapses in the emergence of ASD-related behavioral and physiological phenotypes.