Shisa7, also known as CKAMP59, is an important protein that acts as an auxiliary subunit for both GABAA receptors (GABAARs) and AMPA receptors [1,3,5,6,7]. For GABAARs, it is involved in regulating receptor trafficking, pharmacology, and gating kinetics, thus playing a crucial role in GABAergic transmission, which is vital for normal brain function [1,2,3,4]. For AMPA receptors, it modulates receptor channel kinetics, influencing glutamatergic synaptic function and plasticity [5]. Genetic models, such as mouse models, are valuable tools for studying Shisa7.

In Shisa7 knockout (KO) mouse models, multiple significant phenotypes have been observed. In juvenile Shisa7 KO mice, α5 -GABAAR-mediated tonic currents are reduced as Shisa7 is crucial for α5 -GABAAR exocytosis [4]. Phospho -deficient knock -in (KI) mice, which mimic a loss -of -function state at a specific phosphorylation site in Shisa7, exhibit decreased α1/α2/α5 -GABAAR surface expression, impaired GABAergic inhibition, and abolished inhibitory long -term potentiation in hippocampal neurons. These KI mice also show hyperactivity, increased grooming, and impaired sleep homeostasis, suggesting a role of Shisa7 phosphorylation in neurodevelopmental behaviors [2]. In the context of glutamatergic synapses, Shisa7 KO mice have faster AMPAR currents in CA1 synapses, reduced long -term potentiation of glutamatergic synapses, and specific deficits in contextual fear memory [5]. In rats, overexpressing Shisa7 in the orbitofrontal cortex (OFC) augmented heroin -seeking behavior and impaired behavioral updating, indicating its potential role in opioid -related behaviors [7].

In conclusion, Shisa7 is essential for regulating both GABAergic and glutamatergic transmission, thereby influencing various physiological and behavioral processes. Studies using KO and KI mouse models have revealed its role in neurodevelopmental behaviors, sleep -related regulation of tonic inhibition, hippocampal synaptic function, and opioid -related behaviors, providing insights into potential mechanisms underlying related diseases.