Activation of Kv7.3 channels in mPFC engram neurons suppresses methamphetamine memory retrieval by reducing excitability and glutamate release in the mPFC-NAc circuit.

Emerging evidence demonstrates that engram cells critically mediate fear memory formation and recall, yet their involvement in addiction memory and the underlying neural circuits remains unclear. Using a doxycycline-dependent RAM system, we selectively labeled engram cells in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) during methamphetamine-induced conditioned place preference (CPP). The data revealed that glutamatergic engram cells in the mPFC exhibit preferential projections to the NAc. Chemogenetic inactivation of this mPFCGlu-NAc engram circuit significantly attenuated methamphetamine(Meth) memory retrieval. Context-induced drug retrieval was suppressed when Kv7.3 (encoded by Kcnq3), a slow voltage-activated K⁺ channel in mPFCGlu-NAc engram neurons, received temporally and position-specific activation. Mechanistic analysis demonstrated that Kv7.3 modulates neuronal excitability, synaptic plasticity, and glutamatergic synaptic transmission by recruiting GluA1-containing AMPA receptors. Additionally, electrochemical findings reveal that Kv7.3 channel activation inhibits transmitter release at the single-cell level. Our data suggested that the mPFC engram cells store Meth contextual memory information, while the K⁺ channel Kv7.3 might regulate Meth memory retrieval, possibly providing a novel target for intervening in drug addiction.