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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.

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The brain extracellular matrix (ECM) has garnered increasing attention as a fundamental component of brain function in a predominantly "neuron-centric" paradigm. Particularly, the perineuronal nets (PNNs), a specialized net-like structure formed by ECM aggregates, play significant roles in brain development and physiology. PNNs enwrap synaptic junctions in various brain regions, precisely balancing new synaptic formation and long-term stabilization, and are highly dynamic entities that change in response to environmental stimuli, especially during the neurodevelopmental period. They are found mainly surrounding parvalbumin (PV)-expressing GABAergic interneurons, being proposed to promote PV interneuron maturation and protect them against oxidative stress and neurotoxic agents. This structural and functional proximity underscores the crucial role of PNNs in modulating PV interneuron function, which is critical for the excitatory/inhibitory balance and, consequently, higher-level behaviours. This review delves into the molecular underpinnings governing PNNs formation and degradation, elucidating their functional interactions with PV interneurons. In the broader physiological context and brain-related disorders, we also explore their intricate relationship with other molecules, such as reactive oxygen species and metalloproteinases, as well as glial cells. Additionally, we discuss potential therapeutic strategies for modulating PNNs in brain disorders.

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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.

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Pannexin-1 (Panx1) hemichannel is a non-selective transmembrane channel that may play important roles in intercellular signaling by allowing the permeation of ions and metabolites, such as ATP. Although recent evidence shows that the Panx1 hemichannel is involved in controlling excitatory synaptic transmission, the role of Panx1 in inhibitory transmission remains unknown. Here, we studied the contribution of Panx1 to the GABAergic synaptic efficacy onto CA1 pyramidal neurons (PyNs) by using patch-clamp recordings and pharmacological approaches in wild-type and Panx1 knock-out (Panx1-KO) mice. We reported that blockage of the Panx1 hemichannel with the mimetic peptide 10Panx1 increases the synaptic level of endocannabinoids (eCB) and the activation of cannabinoid receptors type 1 (CB1Rs), which results in a decrease in hippocampal GABAergic efficacy, shifting excitation/inhibition (E/I) balance toward excitation and facilitating the induction of long-term potentiation. Our finding provides important insight unveiling that Panx1 can strongly influence the overall neuronal excitability and play a key role in shaping synaptic changes affecting the amplitude and direction of plasticity, as well as learning and memory processes.

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Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABAA receptors (α5-GABAAR), which are expressed mainly by pyramidal neurons in the hippocampus, have been proposed as a potential target to treat these psychiatric disorders. Here, we evaluated the effects produced by GL-II-73 and SH-053-2'F-R-CH3 (1, 5, and 10 mg/kg), two positive allosteric modulators of α5-GABAAR in behavioral tests sensitive to drugs with anxiolytic, antidepressant, and antipsychotic properties in male and female C57BL/6 mice. In both males and females, GL-II-73 produced an anxiolytic-like effect in the elevated plus-maze (EPM) and novelty-suppressed feeding and a rapid and sustained antidepressant-like effect in the forced swim test. GL-II-73 also induced antipsychotic-like effects in males indicated by attenuating MK-801-induced hyperlocomotion and prepulse inhibition (PPI) disruption. However, GL-II-73 per se increased locomotor activity and impaired fear memory extinction in males and females and PPI in males. On the other hand, SH-053-2'F-R-CH3 induced anxiolytic-like effects in the EPM and facilitated fear memory extinction in males. Contrary to GL-II-73, SH-053-2'F-R-CH3 attenuated MK-801-induced hyperlocomotion and PPI disruption in females but not in males. Neither of these drugs induced rewarding effects or impaired motor coordination. These findings suggest that GL-II-73 and SH-053-2'F-R-CH3 cause distinct sex-dependent behavioral responses and support continued preclinical research on the potential of positive allosteric modulators of α5-GABAAR for the treatment of psychiatric disorders.

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Early in development, neural systems have primarily excitatory coupling, where even GABAergic synapses are excitatory. Many of these systems exhibit spontaneous episodes of activity that have been characterized through both experimental and computational studies. As development progress the neural system goes through many changes, including synaptic remodeling, intrinsic plasticity in the ion channel expression, and a transformation of GABAergic synapses from excitatory to inhibitory. What effect each of these, and other, changes have on the network behavior is hard to know from experimental studies since they all happen in parallel. One advantage of a computational approach is that one has the ability to study developmental changes in isolation. Here, we examine the effects of GABAergic synapse polarity change on the spontaneous activity of both a mean field and a neural network model that has both glutamatergic and GABAergic coupling, representative of a developing neural network. We find some intuitive behavioral changes as the GABAergic neurons go from excitatory to inhibitory, shared by both models, such as a decrease in the duration of episodes. We also find some paradoxical changes in the activity that are only present in the neural network model. In particular, we find that during early development the inter-episode durations become longer on average, while later in development they become shorter. In addressing this unexpected finding, we uncover a priming effect that is particularly important for a small subset of neurons, called the "intermediate neurons." We characterize these neurons and demonstrate why they are crucial to episode initiation, and why the paradoxical behavioral change result from priming of these neurons. The study illustrates how even arguably the simplest of developmental changes that occurs in neural systems can present non-intuitive behaviors. It also makes predictions about neural network behavioral changes that occur during development that may be observable even in actual neural systems where these changes are convoluted with changes in synaptic connectivity and intrinsic neural plasticity.