Perineuronal nets as regulators of parvalbumin interneuron function: Factors implicated in their formation and degradation.

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.

An alpha 5-GABAa receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in an animal model for autism.

Autism Spectrum Disorders (ASD) 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 A Rs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in a rat model for autism based on in utero VPA exposure. 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. 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. Male and female adult 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 α5-GABA A Rs positive allosteric modulators may effectively attenuate some core ASD symptoms.

Cannabidiol attenuates the expression of conditioned place aversion induced by naloxone-precipitated morphine withdrawal through the activation of 5-HT1A receptors.

The misuse of and addiction to opioids are serious public health problems in some countries, such as the USA. Drug addiction is a chronic and relapsing medical condition that involves motivational and memory-related processes due to the strong associations between drugs and consuming-related stimuli. These stimuli usually trigger continuous and compulsive use and are associated with relapses after periods of withdrawal. Several factors contribute to relapse, including withdrawal-induced mood changes. Therefore, drugs attenuating withdrawal-induced affective alterations could be useful alternative treatments for relapse prevention. Cannabidiol (CBD), a non-psychotomimetic component from the Cannabis sativa plant, has anti-anxiety and anti-stress properties and has been investigated as an alternative for the treatment of several mental disorders, including drug addiction. Here, we evaluated if CBD administered 30 min prior to test for a conditioned place aversion (CPA) would attenuate the aversion induced by morphine withdrawal precipitated by the opioid receptor antagonist naloxone in male C57BL/6 mice. We also investigated if this effect involves the activation of 5-HT1A receptors, a mechanism previously associated with CBD anti-aversive effects. As expected, morphine-treated mice spent less time exploring the compartment paired with the naloxone-induced withdrawal, indicating a CPA induced by naloxone-precipitated morphine withdrawal. This effect was not observed in animals treated with CBD, at 30 and 60 mg/kg, prior to the CPA test, indicating that CBD attenuated the expression of CPA induced by naloxone-precipitated morphine withdrawal. Pretreatment with the 5-HT1A receptor antagonist WAY100635 (0.3 mg/kg) blocked CBD effects. Our findings suggest that CBD may reduce the expression of a previously established conditioned aversion induced by morphine withdrawal by a mechanism involving the activation of 5-HT1A receptors. Thus, CBD may be a therapeutic alternative for preventing relapse to opioid addiction by decreasing withdrawal-induced negative affective changes.

Distinct sex-dependent behavioral responses induced by two positive allosteric modulators of alpha 5 subunit-containing GABAA receptors.

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.