Shisa7, also known as CKAMP59, is an important protein associated with both GABA_A receptors and AMPA receptors [1,3,5,6,7]. It plays a crucial role in regulating neurotransmission, as it modulates the trafficking, pharmacology, and gating kinetics of GABA_A receptors, which are vital for fast inhibitory transmission in the brain [1,3]. Additionally, it impacts glutamatergic synapses by interacting with synaptic AMPA receptors and regulating their channel kinetics [5].

In gene-knockout (KO) mouse models, several significant findings have emerged. Shisa7-deficient mice show reduced GABAergic inhibition in hippocampal neurons due to decreased surface expression of α1/α2/α5-GABA_A receptors, along with abolished chemically induced inhibitory long-term potentiation, and exhibit hyperactivity, increased grooming, and impaired sleep homeostasis [2]. Juvenile Shisa7 KO mice have significantly reduced α5-GABA_A receptor-mediated tonic currents, as Shisa7 is crucial for α5-GABA_A receptor exocytosis [4]. In Shisa7 KO mice, faster AMPAR currents are observed in CA1 synapses, along with reduced long-term potentiation of glutamatergic synapses and deficits in contextual fear memory [5]. Overexpressing Shisa7 in the orbitofrontal cortex of rats augmented heroin-seeking behavior and impaired behavioral updating [7].

In conclusion, Shisa7 is essential for regulating both inhibitory and excitatory neurotransmission. The use of Shisa7 KO mouse models has revealed its significance in neurodevelopmental behaviors, sleep-related regulation of tonic inhibition, hippocampal synaptic plasticity, and memory recall, as well as in behaviors related to opioid use disorder. These findings provide insights into the molecular mechanisms underlying these biological processes and disease conditions.