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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. 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]

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 netlike 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. [ABSTRACT FROM AUTHOR]

This Editorial highlights an article by Gulchina and colleagues in the current issue of the Journal of Neurochemistry, in which the authors describe molecular and epigenetic changes in the developing prefrontal cortex of the rats exposed to methylazoxymethanol acetate (MAM). They found an NMDAR hypofunction present in the prefrontal cortex of juvenile MAM rats which was associated with abnormal epigenetic regulation of the Grin2b gene. These changes may be related to early cognitive impairments observed in MAM rats and schizophrenia patients. [ABSTRACT FROM AUTHOR]

Cannabidiol ( CBD), one of the main components of Cannabis sp., presents clinical and preclinical anxiolytic properties. Recent results using the marble-burying test ( MBT) suggest that CBD can also induce anticompulsive-like effects. Meta-chloro-phenyl-piperazine ( mCPP) is a nonspecific serotonergic agonist (acting mainly at 5 HT1A, 5 HT2C and 5 HT1D receptors) reported to increase symptoms in OCD patients and block the anticompulsive-like effect of serotonin reuptake inhibitors ( SRIs) in animal models. The aim of this study was to investigate the interference of CBD on mCPP effects in repetitive burying. Administration of mCPP showed dual effects in the MBT, increasing the number of buried marbles at lower (0.1 mg/kg) while decreasing it at higher doses (1 mg/kg), an effect not related to a general increase in anxiety-like behavior. As found previously, CBD (30 mg/kg) and the positive control fluoxetine ( FLX; 10 mg/kg) decreased burying behavior without changing general exploratory activity. A similar effect was found when subeffective doses of CBD (15 mg/kg) and FLX (3 mg/kg) were administered together. These subeffective doses alone were also able to block mCPP-induced repetitive burying. The results, in addition to reinforcing a possible anticompulsive effect of CBD, also suggest that mCPP-induced repetitive burying could be a useful test for the screening of compounds with presumed anticompulsive properties. [ABSTRACT FROM AUTHOR]

The insular cortex ( IC) has been reported to be involved in the modulation of memory and autonomic and defensive responses. However, there is conflicting evidence about the role of the IC in fear conditioning. To explore the IC involvement in both behavioral and autonomic responses induced by contextual fear conditioning, we evaluated the effects of the reversible inhibition of the IC neurotransmission through bilateral microinjections of the non-selective synapse blocker Co Cl2 (1 m m) 10 min before or immediately after the conditioning session or 10 min before re-exposure to the aversive context. In the conditioning session, rats were exposed to a footshock chamber (context) and footshocks were used as the unconditioned stimulus. Forty-eight hours later, the animals were re-exposed to the aversive context for 10 min, but no shock was given. Behavioral (freezing) as well as cardiovascular (arterial pressure and heart rate increases) responses induced by re-exposure to the aversive context were analysed. It was observed that the local IC neurotransmission inhibition attenuated freezing and the mean arterial pressure and heart rate increase of the groups that received the Co Cl2 either immediately after conditioning or 10 min before re-exposure to the aversive context, but not when the Co Cl2 was injected before the conditioning session. These findings suggest the involvement of the IC in the consolidation and expression of contextual aversive memory. However, the IC does not seem to be essential for the acquisition of memory associated with aversive context. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The bed nucleus of the stria terminalis (BNST) is a limbic structure that is involved in the expression of conditioned contextual fear. Among the numerous neural inputs to the BNST, noradrenergic synaptic terminals are prominent and some evidence suggests an activation of this noradrenergic neurotransmission in the BNST during aversive situations. Here, we have investigated the involvement of the BNST noradrenergic system in the modulation of behavioural and autonomic responses induced by conditioned contextual fear in rats. EXPERIMENTAL APPROACH Male Wistar rats with cannulae bilaterally implanted into the BNST were submitted to a 10 min conditioning session (6 footshocks, 1.5 ma/ 3 s). Twenty-four hours later freezing and autonomic responses (mean arterial pressure, heart rate and cutaneous temperature) to the conditioning box were measured for 10 min. The adrenoceptor antagonists were administered 10 min before the re-exposure to the aversive context. KEY RESULTS L-propranolol, a non-selective β-adrenoceptor antagonist, and phentolamine, a non-selective α-adrenoceptor antagonist, reduced both freezing and autonomic responses induced by aversive context. Similar results were observed with CGP20712, a selective β1-adrenoceptor antagonist, and WB4101, a selective α1-antagonist, but not with ICI118,551, a selective β2-adrenoceptor antagonist or RX821002, a selective α2-antagonist. CONCLUSIONS AND IMPLICATIONS These findings support the idea that noradrenergic neurotransmission in the BNST via α1- and β1-adrenoceptors is involved in the expression of conditioned contextual fear. [ABSTRACT FROM AUTHOR]

Background and Purpose: The bed nucleus of the stria terminalis (BNST) is a limbic structure that is involved in the expression of conditioned contextual fear. Among the numerous neural inputs to the BNST, noradrenergic synaptic terminals are prominent and some evidence suggests an activation of this noradrenergic neurotransmission in the BNST during aversive situations. Here, we have investigated the involvement of the BNST noradrenergic system in the modulation of behavioural and autonomic responses induced by conditioned contextual fear in rats.Experimental Approach: Male Wistar rats with cannulae bilaterally implanted into the BNST were submitted to a 10 min conditioning session (6 footshocks, 1.5 ma/ 3 s). Twenty-four hours later freezing and autonomic responses (mean arterial pressure, heart rate and cutaneous temperature) to the conditioning box were measured for 10 min. The adrenoceptor antagonists were administered 10 min before the re-exposure to the aversive context.Key Results: L-propranolol, a non-selective β-adrenoceptor antagonist, and phentolamine, a non-selective α-adrenoceptor antagonist, reduced both freezing and autonomic responses induced by aversive context. Similar results were observed with CGP20712, a selective β(1) -adrenoceptor antagonist, and WB4101, a selective α(1) -antagonist, but not with ICI118,551, a selective β(2) -adrenoceptor antagonist or RX821002, a selective α(2) -antagonist.Conclusions and Implications: These findings support the idea that noradrenergic neurotransmission in the BNST via α(1) - and β(1) -adrenoceptors is involved in the expression of conditioned contextual fear. [ABSTRACT FROM AUTHOR]