Shengkai Ding

Maintaining GABAergic inhibition within physiological limits in the medial prefrontal cortex (mPFC) is critical for working memory. While synaptic GABA_AR typically mediate the primary component of mPFC inhibition, the role of extrasynaptic δ-GABA_AR in working memory remains unclear. To investigate this, we used fiber photometry to examine the effects of δ-GABA_AR in freely moving mice. Our results indicate that the loss of δ-GABA_AR expression leads to learning and memory impairment. Specifically, activation of δ-GABA_AR impaired learning and memory in WT mice but enhanced learning and memory in δ^+/− knockout mice. Furthermore, δ-GABA_AR activation increased calcium activity in the mPFC pyramidal neurons, an effect not observed in δ-Cas9-sgRNA virus-infected mice. Collectively, these findings suggest that δ-GABA_AR deficiency impairs learning and memory by modulating the excitability of pyramidal neurons in the mPFC. These results delineate the functional contribution of δ-GABA_AR to learning and memory, suggesting their role extends beyond the mere maintenance of information.