KCNQ2/3 Regulates the Synaptic Remodeling Associated with Drug Seeking in Addiction

Zhou, X.; Zhang, X.; Funahashi, Y.; Tsuboi, D.; Takano, T.; Kubota, H.; Yokoyama, C. T.; Nabeshima, T.; Yamada, K.; Kaibuchi, K.; Nagai, T.

doi:10.64898/2026.06.14.732187

bioRxiv · 10.64898/2026.06.14.732187

KCNQ2/3 Regulates the Synaptic Remodeling Associated with Drug Seeking in Addiction

Zhou, X.·Zhang, X.·Funahashi, Y.·Tsuboi, D.·Takano, T.·Kubota, H.·Yokoyama, C. T.·Nabeshima, T.·Yamada, K.·Kaibuchi, K.·Nagai, T.

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Abstract

Drug-seeking behavior during withdrawal represents a critical obstacle to addiction treatment. In the nucleus accumbens, hyperactive dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs) promote cocaine-seeking through aberrant synaptic remodeling, including synapse formation and calcium-permeable AMPA receptor (CP-AMPAR) insertion. However, the intermediate molecular control mechanism remains unclear. We identified KCNQ2/3 potassium channels as key regulators of synaptic pathology during withdrawal. Cocaine-conditioned mice showed increased spine density, enhanced surface CP-AMPAR, and elevated neuronal activity 14 days after withdrawal. These phenotypes were reversed by repeated administration of KCNQ2/3 openers or D1R-MSN-specific expression of constitutively active KCNQ2. Functional restoration of KCNQ2/3 suppressed cocaine-seeking behavior and normalized D1R-MSN excitability. These findings suggest that sustained KCNQ2/3 deactivation drives synaptic remodeling during withdrawal, while channel activation offers a potential therapeutic strategy. Furthermore, the results position KCNQ2/3 as a master regulator of drug-seeking behavior and channel activation in D1R-MSNs as a logical target for relapse prevention in addiction.

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Zhou, X., Zhang, X., Funahashi, Y., Tsuboi, D., Takano, T., Kubota, H., Yokoyama, C. T., Nabeshima, T., Yamada, K., Kaibuchi, K., Nagai, T.. 2026-06-16. KCNQ2/3 Regulates the Synaptic Remodeling Associated with Drug Seeking in Addiction. https://doi.org/10.64898/2026.06.14.732187

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