450. CEREBELLAR α6GABAA RECEPTOR AS A POTENTIAL THERAPEUTIC TARGET FOR RELIEVING CORE SYMPTOMS OF AUTISM: A PRECLINICAL STUDY IN PRENATAL VALPROIC ACID-EXPOSURE RATS

Abstract Background Autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by social impairment and repetitive behaviors, remains an unmet medical need. Cerebellar abnormalities, particularly loss or hypofunction of Purkinje cells (PCs), were reported in ASD patients and animal models. The α6 subunit-containing GABAA receptors (α6GABAARs) are densely expressed at cerebellar Golgi cells-granule cells (GCs) synapses. GCs regulate PC activity and the cerebellar output via the downstream deep cerebellar nuclei (DCN). Aims & Objectives Previously, we identified an α6GABAAR-highly selective positive allosteric modulator (PAM), DK-I-56-1 (DK). It is druggable and exhibits satisfied pharmacokinetic and safety pharmacology profiles. 1 Here, we explored the potential of DK in treating core symptoms of ASD employing a well-recognized animal model, prenatal valproic acid (VPA)-exposure juvenile rats. We hypothesized that DK enhances GABAergic transmission on GCs, thus restoring impaired PC activity and DCN outputs, ultimately rescues cortical excitatory/inhibitory (E/I) balance and alleviates ASD-associated symptoms. Method VPA (500 mg/kg) or saline was i.p. injected into pregnant rats on E12.5. We compared social behaviors, repetitive behaviors, and autism composite scores, calculated by composing the normalized z-score in each behavior, between VPA and saline offspring groups treated with DK or vehicle. Social behaviors, including sociability and social preference, were assessed by the three-chamber social interaction test. Repetitive behaviors were evaluated by grooming and rearing in the open-field test. Results Male, but not female, juvenile rats prenatally exposed to VPA, but not saline, showed significantly impaired sociability and social preference, repetitive behaviors, and fewer PCs in the cerebellum. Acute treatment with DK (10 mg/kg, i.p.) on P21, but not vehicle, for 30 minutes significantly improved sociability, but not social preference, in the VPA group. Daily DK treatment for five, but not three, days completely restored two social behaviors and repetitive behaviors in the VPA offspring group, thus normalizing their composite scores to the level in the saline-control group. This preventive effect of DK was antagonized by furosemide, an α6GABAAR antagonist, when intra-cerebellarly injected before DK treatment. Discussion & Conclusions In the VPA model, we reproduced the core deficits (social impairment and repetitive behaviors) of ASD in males but not females and found reduced PC numbers in their cerebellums. DK, at a dose without benzodiazepine-like adverse effects,2,3 was enough to improve sociability, while a consecutive treatment for five days prevented both social deficits and repetitive behaviors. DK’s therapeutic effects are mediated via cerebellar α6GABAARs, highlighting their role in the pathogenesis of ASD and the potential of α6GABAAR PAMs as a therapeutic strategy for alleviating core features of ASD.