α6GABA_A receptors as novel targets for ADHD therapy: A proof-of-concept study in MK-801-treated juvenile mice

Cerebellar abnormalities have been associated with attention-deficit/hyperactivity disorder (ADHD) in human studies. Animal models also implicate cerebellar microcircuit dysfunction, particularly reduced inhibitory control of granule cells (GCs) in mice lacking Git1, an ADHD risk gene. Excitatory GCs are the most abundant neuronal population in the cerebellum and are enriched in α6 subunit-containing GABA_A (α6GABA_A) receptors. Thus, α6GABA_A receptor-selective positive allosteric modulators (PAMs), such as pyrazoloquinolinones (PQs), may represent a novel therapeutic approach for ADHD. Here, we tested this hypothesis using PQ Compound 6 in juvenile (P28) ICR mice treated with dizocilpine (MK-801, 0.2 mg/kg, intraperitoneally, i.p.), an NMDA receptor antagonist. In both sexes, MK-801 induced behavioral abnormalities resembling the three core symptoms of ADHD- hyperlocomotion, impulsivity, and inattention-as assessed by locomotor activity, cliff avoidance reaction, and novel object recognition tests, respectively. Compound 6 (3 mg/kg, i.p.) normalized these ADHD-like behavioral impairments. Atomoxetine, an approved ADHD medication, also attenuated ADHD-like phenotypes, although with sedative effects. The therapeutic-like effects of Compound 6 were abolished by intracerebellar microinjection of furosemide, an α6GABA_A receptor antagonist, and were absent in Gabra6 (α6-encoding gene)-knockout mice, indicating that positive modulation of cerebellar α6GABA_A receptors underlies the observed behavioral improvements. Together, these findings provide proof-of-concept that enhancing cerebellar α6GABA_A receptor-mediated inhibition can ameliorate ADHD-relevant behavioral impairments and highlight α6GABA_A receptor-selective PAMs as a potential pharmacotherapeutic strategy for ADHD.