Transgenic expression of BK channel auxiliary LRRC26 subunit in the forebrain causes locomotor hyperactivity and cognitive defects

The large-conductance, Ca²⁺- and voltage-activated K⁺ (BK) channels are widely distributed in the central nervous system, where they play diverse roles in regulating brain activity. The γ1 (LRRC26) subunit functions as a potent activator of BK channels, inducing a large shift in the voltage dependence of channel activation toward the hyperpolarized direction. Given the large conductance of BK channels, their activators have promising therapeutic potential for the treatment of various diseases. To investigate the impact of activator-induced hyperactivity of BK channels on brain function, we generated conditional hLRRC26 transgenic mice in which recombinant human LRRC26 is expressed in the forebrain under the control of the CaMKIIα promoter and the tetracycline Tet-Off system. Experiments included mice of both sexes and data were pooled across sexes, as no obvious sex-dependent effects were detected. Histological analysis of mice with post-weaning doxycycline withdrawal confirmed expression of hLRRC26 in the forebrain, with strong expression detected in regions including the hippocampus, isocortex, and striatum. Behavioral tests demonstrated that long-term hLRRC26 expression in the forebrain resulted in locomotor hyperactivity, cognitive deficits, and some anxiety- and depression-like behaviors. At 2–4 months of age, hLRRC26 transgenic mice exhibited significantly elevated locomotor activity, with increased movement distance in the open field test, despite displaying shorter strides in the footprint test. These mice also showed impaired learning performance in the water maze, novel object recognition, and rotarod tests compared to control groups. At 12–14 months of age, transgenic mice continued to display locomotor hyperactivity and cognitive deficits. In conclusion, hLRRC26 transgenic mice demonstrated heightened locomotor activity and cognitive impairments, revealing potential ADHD-like neurological consequences of BK channel hyperactivity. Significance Statement BK channels are widely distributed throughout the central nervous system, where they play crucial roles in regulating brain activity. However, the physiological and health implications of BK channel gain-of-function (GOF) remain inadequately understood. In this study, we generated transgenic mice that allow conditional and inducible expression of human LRRC26 (hLRRC26), an auxiliary subunit and potent activator of BK channels. Our findings reveal that transgenic mice with long-term hLRRC26 expression in the forebrain exhibit heightened locomotor activity and cognitive impairments, revealing potential ADHD-like neurological consequences of BK channel hyperactivity.