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Background Stress has become a common public health concern, contributing to the rising prevalence of psychiatric disorders. Understanding the impact of stress considering critical variables, such as age, sex, and individual differences, is of the utmost importance for developing effective intervention strategies. Methods Stress effects (daily footshocks for 10 days) during adolescence (postnatal day [PND] 31–40) and adulthood (PND 65–74) were investigated on behavioral outcomes and parvalbumin (PV)-expressing GABAergic interneurons and their associated perineuronal nets (PNNs) in the prefrontal cortex of male and female mice 5 weeks post stress. Results In adulthood, adolescent stress induced behavioral alterations in male mice, including anxiety-like behaviors, social deficits, cognitive impairments, and altered dopamine system responsivity. Applying integrated behavioral z-score analysis, we identified sex-specific differences in response to adolescent stress, with males displaying greater vulnerability than females. Furthermore, adolescent-stressed male mice showed decreased PV+ and PNN+ cell numbers and PV+/PNN+ colocalization, while in females, adolescent stress reduced prefrontal PV+/PNN+ colocalization in the prefrontal cortex. Further analysis identified distinct behavioral clusters, with certain females demonstrating resilience to adolescent stress-induced deficits in sociability and PV+ cell number. Adult stress in male and female mice did not cause long-lasting changes in behavior and PV+ and PNN+ cell number. Conclusion Our findings indicate that the timing of stress, sex, and individual variabilities seem to be determinants for the development of behavioral changes associated with psychiatric disorders, particularly in male mice during adolescence. [ABSTRACT FROM AUTHOR]

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. Lay Summary: Autism spectrum disorders (ASDs) are a group of conditions characterized by abnormalities in social interaction and communication, and repetitive behaviors. These deficits often stem from underlying imbalances in the brain's chemical messengers. Efforts to address it have led researchers to explore substances that can improve brain function in ASD. One promising candidate is GABA, a neurotransmitter critical for brain communication. Basic research has indicated that boosting GABA activity may alleviate some of the core ASD symptoms. Furthermore, some studies have uncovered a potential link between GABA and dopamine, another neurotransmitter implicated in ASD symptoms. In this study, we investigated the effects of SH‐053‐2′F‐R‐CH3, a drug that can potentiate GABA effects through the modulation of alpha 5‐containing GABAA receptors in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. Unlike female rats, male rats exhibited improved sociability and cognitive function after the administration of SH‐053‐2′F‐R‐CH3. Additionally, we found an increased activity of the midbrain dopamine system in VPA‐exposed rats, which was not attenuated by SH‐053‐2′F‐R‐CH3. Overall, despite sex differences, our findings indicate that boosting GABA activity through alpha 5‐containing GABAA receptors may attenuate some ASD symptoms. [ABSTRACT FROM AUTHOR]

Background Consistent with postmortem findings in patients, most animal models for schizophrenia (SCZ) present abnormal levels of parvalbumin (PV), a marker of fast-spiking GABAergic interneurons, in the prefrontal cortex (PFC) and hippocampus (HIP). However, there are discrepancies in the literature. PV reductions lead to a functional loss of PV interneurons, which is proposed to underly SCZ symptoms. Given its complex etiology, different categories of animal models have been developed to study SCZ, which may distinctly impact PV levels in rodent brain areas. Study Design We performed a quantitative meta-analysis on PV-positive cell number/density and expression levels in the PFC and HIP of animal models for SCZ based on pharmacological, neurodevelopmental, and genetic manipulations. Results Our results confirmed that PV levels are significantly reduced in the PFC and HIP regardless of the animal model. By categorizing into subgroups, we found that all pharmacological models based on NMDA receptor antagonism decreased PV-positive cell number/density or PV expression levels in both brain areas examined. In neurodevelopmental models, abnormal PV levels were confirmed in both brain areas in maternal immune activation models and HIP of the methylazoxymethanol acetate model. In genetic models, negative effects were found in neuregulin 1 and ERBB4 mutant mice in both brain regions and the PFC of dysbindin mutant mice. Regarding sex differences, male rodents exhibited PV reductions in both brain regions only in pharmacological models, while few studies have been conducted in females. Conclusion Overall, our findings support deficits in prefrontal and hippocampal PV interneurons in animal models for SCZ. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex neuropsychiatric disorder that has undergone significant advancements in its treatment. However, there are still many aspects of symptom management and prevention that could benefit from new developments in psychopharmacology. One potential avenue is the use of cannabidiol (CBD), a major phytocannabinoid found in the cannabis plant. Preliminary evidence suggests that CBD could effectively treat certain symptoms of the disorder with fewer side effects than conventional antipsychotics. This article provides the reader with an in-depth discussion of the current scientific evidence concerning the use of CBD in the treatment of schizophrenia. [Psychiatr Ann. 2023;53(6):252–255.] [ABSTRACT FROM AUTHOR]