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Background: Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle. Methods: We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Nav) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Nav activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Nav in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo. Results: We demonstrated that Nav is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Nav made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Nav substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Nav positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Nav. Conclusions: This insight positions Nav as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorders (NDDs) include a broad spectrum of pathological conditions that affect >4% of children worldwide, share common features and present a variegated genetic origin. They include clinically defined diseases, such as autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), motor disorders such as Tics and Tourette's syndromes, but also much more heterogeneous conditions like intellectual disability (ID) and epilepsy. Schizophrenia (SCZ) has also recently been proposed to belong to NDDs. Relatively common causes of NDDs are copy number variations (CNVs), characterised by the gain or the loss of a portion of a chromosome. In this review, we focus on deletions and duplications at the 16p11.2 chromosomal region, associated with NDDs, ID, ASD but also epilepsy and SCZ. Some of the core phenotypes presented by human carriers could be recapitulated in animal and cellular models, which also highlighted prominent neurophysiological and signalling alterations underpinning 16p11.2 CNVs-associated phenotypes. In this review, we also provide an overview of the genes within the 16p11.2 locus, including those with partially known or unknown function as well as non-coding RNAs. A particularly interesting interplay was observed between MVP and MAPK3 in modulating some of the pathological phenotypes associated with the 16p11.2 deletion. Elucidating their role in intracellular signalling and their functional links will be a key step to devise novel therapeutic strategies for 16p11.2 CNVs-related syndromes. [ABSTRACT FROM AUTHOR]

This editorial titled "Cellular and molecular mechanisms in social and repetitive behaviors: a focus on cortico-striatal circuitry" explores the neural basis of social and repetitive behaviors, particularly the involvement of the basal ganglia. It discusses the role of the dorsal striatum and nucleus accumbens in social behavior and the changes in cortico-striatal connections seen in autism spectrum disorder and schizophrenia. The editorial also examines the contribution of different types of striatal cells, such as medium spiny neurons, to social and repetitive behaviors, and their potential role in neurodevelopmental disorders. It discusses the involvement of dopaminergic signaling and specific genes, such as the CHL1 gene, in these disorders. Additionally, it highlights the significance of copy number variants at the 16p11.2 chromosomal region in neurodevelopmental disorders and discusses the genes within this region. The review emphasizes the importance of understanding the neural mechanisms behind social and motor behaviors to develop more effective interventions for these conditions. [Extracted from the article]

Background and Purpose: Regulator of G‐protein signalling 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signalling. Here, we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signalling and if this modulation has relevance for l‐Dopa‐induced dyskinesia. Experimental Approach HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small‐molecule NOP agonist AT‐403, using D1‐stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with either N/OFQ or AT‐403 in the presence of the experimental RGS4 chemical probe, CCG‐203920, and D1‐stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG‐203920 was co‐administered with AT‐403 and l‐Dopa to 6‐hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. Key Results: RGS4 expression reduced NOFQ and AT‐403 potency and efficacy in HEK293T cells. CCG‐203920 increased N/OFQ potency in primary rat striatal neurons and potentiated AT‐403 response in mouse striatal slices. CCG‐203920 enhanced AT‐403‐mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor‐improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by l‐Dopa. l‐Dopa acutely up‐regulated RGS4 in the lesioned striatum. Conclusions and Implications: RGS4 physiologically inhibits NOP receptor signalling. CCG‐203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 up‐regulation occurring during dyskinesia expression. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc [ABSTRACT FROM AUTHOR]