An alpha 5-GABAA receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero

Abstract

Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABA_A receptors (α5-GABA_ARs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2'F-R-CH3 could attenuate these changes. SH-053-2'F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2'F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2'F-R-CH3. Despite sex differences, our findings indicate that α5-GABA_ARs positive allosteric modulators may effectively attenuate some core ASD symptoms.

Keywords: GABAA receptors; SH‐053‐2′F‐R‐CH3; VPA; autism; excitatory‐inhibitory balance.

Figure 1 –

(A) In utero VPA exposure increased self-grooming time in males and females during early adolescence, (B) but not in adulthood. However, (C) a decrease in social interaction was observed in adult male and female VPA rats. Regarding cognition, (D) only male VPA-exposed rats presented decreased recognition memory in the NOR test (n=8–10/group). *p<0.05 vs. saline rats, two-way ANOVA followed by Tukey’s post-test.

Figure 2 –

In utero VPA caused males and females to show (A) an increased number of spontaneously active VTA DA neurons (n= 6 animals/group), (B) with no change in the firing rate (C) and % of spikes in burst. In addition, (D) no marked changes were found for the average ISI distribution (males – saline: 56 DA neurons, VPA: 72 DA neurons; females – saline: 57 DA neurons, VPA: 82 DA neurons). ISI histograms have bin widths of 20 ms. *p<0.05 vs. saline rats, two-way ANOVA followed by Tukey’s post-test.

Figure 3 –

(A) SH-053–2’F-R-CH3 attenuated impairment in the social interaction test in male, (B) but not in female rats exposed to VPA. (C) SH-053–2’F-R-CH3 also reverted deficits in novel object recognition memory in male VPA rats. (D) Female VPA rats did not present deficits in the NOR test. In addition, the increased VTA DA neuron population activity found in (E) male and (F) female VPA rats was not changed by SH-053–2’F-R-CH3 (behavioral tests - n=5–10 animals/group; VTA recordings - n=5/group). *p<0.05, two-way ANOVA followed by Tukey’s post-test.