α6GABAA receptors as novel targets for ADHD therapy: A proof-of-concept study in MK-801-treated juvenile mice
Y.-H. Lee1, C.-C. Lu1, H.-J. Lee1, A. Mouri2, D. Sharmin3, J. Cook3, T. Nabeshima2, W. Sieghart4, L.-C. Chiou1
1National Taiwan University, Graduate Institute of Pharmacology, College of Medicine, Taipei, Taiwan, 2Fujita Health University, Graduate School of Medical Sciences, Aichi, Japan, 3University of Wisconsin-Milwaukee, Department of Chemistry and Biochemistry, Milwaukee, WI, United States, 4Medical University Vienna, Department of Molecular Neurosciences, Vienna, Austria
Background: Attention-deficit hyperactivity disorder (ADHD) is associated with cerebellar abnormalities and altered cortico–striatal–cerebellar circuitry. Animal models indicate cerebellar microcircuit dysfunction, including reduced inhibitory control of granule cells (GCs). GABAA receptors containing the Gabra6-encoded α6 subunit (α6GABAARs) are highly enriched in the cerebellar GCs and regulate their excitability.
Aims & Objectives: Here, we aimed to investigate whether pharmacological enhancement of α6GABAAR function alleviates ADHD-like behaviors.
Method: Juvenile (P28) ICR mice were treated with the NMDA receptor channel blocker MK-801 (0.2 mg·kg-1 i.p.) to induce behaviorals reminensent to the three ADHD core symptoms–hyperlocomotion, impulsivity, and inattention phenotypes–using locomotor activity, cliff avoidance reaction, and novel object recognition tests, respectively. The α6GABAAR-selective positive allosteric modulator (PAM) Compound 6 (3 mg·kg-1 i.p.) was assessed in these three ADHD-like behaviors for its potential in ADHD treatment, with atomoxetine as a positive control. Pharmacological and genetic specificity were evaluated by intra-cerebellar administration of furosemide, an α6GABAAR antagonist, and by Gabra6-knockout mice.
Results: MK-801 induced robust hyperlocomotion, increased impulsive behavior, and impaired novel object recognition. Compound 6 normalized these ADHD-like behavioral abnormalities. The effects of Compound 6 were mimicked by atomoxetine, an ADHD medication, blocked by intra-cerebellar administration of furosemide, and absent in Gabra6-knockout mice.
Discussion & Conclusions: These results demonstrate that positive modulation of cerebellar α6GABAARs effectively counteracts ADHD-like core symptom behaviors in juvenile mice. These findings highlight α6GABAAR-selective PAMs as a promising therapeutic strategy and support cerebellar α6GABAAR modulation as a relevant target for ADHD treatment.
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