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bioRxiv · 10.1101/2025.03.27.645613

Synaptic editing of frontostriatal circuitry prevents excessive grooming in SAPAP3-deficient mice

Walder-Christensen, K. K.·Soliman, H. A.·Calakos, N.·Dzirasa, K.
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Abstract

Synaptic dysfunction has been implicated as a key mechanism underlying the pathophysiology of psychiatric disorders. Most pharmacological therapeutics for schizophrenia, autism spectrum disorder, obsessive-compulsive disorder, and major depressive disorder temporarily augment chemical synapse function. Nevertheless, medication non-compliance is a major clinical challenge, and behavioral dysfunction often returns following pharmacotherapeutic discontinuation. Here, we deployed a designer electrical synapse to edit a single class of chemical synapses in a genetic mouse model of obsessive-compulsive disorder (OCD). Editing these synapses in juvenile mice normalized circuit function and prevented the emergence of pathological repetitive behavior in adulthood. Thus, we establish precision circuit editing as a putative strategy for preventative psychotherapeutics.

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Walder-Christensen, K. K., Soliman, H. A., Calakos, N., Dzirasa, K.. 2025-03-29. Synaptic editing of frontostriatal circuitry prevents excessive grooming in SAPAP3-deficient mice. https://doi.org/10.1101/2025.03.27.645613

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