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.
A GABA-boosting drug improved social play and memory only in male autism-model rats, showing sex limits before human trials.
01Research in Context
What this study did
Scientists gave pregnant rats valproic acid. This drug creates pups that act like autism models.
They later injected some adult pups with SH-053, a pill that boosts a tiny GABA spot called the alpha-5 receptor.
The team then watched how the rats played, sniffed new friends, and remembered objects.
What they found
The drug helped male rats socialize and remember toys better.
It did nothing for female rats or for their hyper dopamine signals.
So the fix is partial and depends on sex.
How this fits with other research
Santrač et al. (2022) ran almost the same test two years earlier. They used a cousin drug, MP-III-022, and saw both sexes improve plus less repetitive grooming. The new study keeps the male win but loses the female and stereotypy gains. The switch in drug and dose may explain the gap.
Hara et al. (2016) gave ADHD meds to VPA mice and lifted social plus memory woes. They did it by raising dopamine. Jesus et al. tried a GABA path and still helped memory, yet dopamine stayed high. Two roads can reach similar social stops.
Brondino et al. (2016) reviewed human GABA pills for autism and found no clear win. The rat promise has not yet jumped to people.
Why it matters
You can’t prescribe SH-053 tomorrow, but you can stay alert for sex-split drug answers. When families ask about new GABA medicines, note that boys might respond while girls could be left out. Keep tracking rodent work; it hints at which receptors your future clients might target.
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02At a glance
03Original 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 GABAA receptors (α5-GABAARs) 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-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.
Autism research : official journal of the International Society for Autism Research, 2024 · doi:10.1002/aur.3178