Gene Deficiency of δ Subunit-Containing GABA Receptor in mPFC Lead Learning and Memory Impairment in Mice.

Maintaining GABAergic inhibition within physiological limits in the medial prefrontal cortex (mPFC) is critical for working memory. While synaptic GABAR typically mediate the primary component of mPFC inhibition, the role of extrasynaptic δ-GABAR in working memory remains unclear. To investigate this, we used fiber photometry to examine the effects of δ-GABAR in freely moving mice. Our results indicate that the loss of δ-GABAR expression leads to learning and memory impairment. Specifically, activation of δ-GABAR impaired learning and memory in WT mice but enhanced learning and memory in δ knockout mice. Furthermore, δ-GABAR 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-GABAR deficiency impairs learning and memory by modulating the excitability of pyramidal neurons in the mPFC. These results delineate the functional contribution of δ-GABAR to learning and memory, suggesting their role extends beyond the mere maintenance of information.