Search

Autism is a neurodevelopmental condition with a range of symptoms that vary in intensity and severity from person to person. Genetic sequencing has identified thousands of genes containing mutations in autistic individuals, which may contribute to the development of autistic symptoms. Several of these genes encode G protein-coupled receptors (GPCRs), which are cell surface expressed proteins that transduce extracellular messages to the intracellular space. Mutations in GPCRs can impact their function, resulting in aberrant signalling within cells and across neurotransmitter systems in the brain. This review summarises the current knowledge on autism-associated single nucleotide variations encoding missense mutations in GPCRs and the impact of these genetic mutations on GPCR function. For some autism-associated mutations, changes in GPCR expression levels, ligand affinity, potency and efficacy have been observed. However, for many the functional consequences remain unknown. Thus, further work to characterise the functional impacts of the genetically identified mutations is required. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc., (© 2023 British Pharmacological Society.)

Osteocalcin (OCN) is a hormone secreted by osteoblasts and has attracted widespread attention for its role in regulating brain function. Clinical studies indicate a positive correlation between levels of circulating OCN and cognitive performance. Indeed, lower circulating OCN has been detected in various neurodegenerative diseases (NDs), while OCN supplementation under certain conditions may improve cognitive function. GPR37, a G protein-coupled receptor, has recently been identified as a receptor for OCN. It exhibits distinct expression patterns across various brain regions and cell types, potentially influencing its functional roles within the brain. Research indicates that GPR37 regulates neuronal migration, cell proliferation, differentiation, and myelination. Furthermore, GPR37 has been shown to mitigate inflammation and apoptosis through various mechanisms, exerting neuroprotective effects. However, its regulatory influence on brain function exhibits inconsistency, highlighting a duality in its actions. Therefore, this review thoroughly summarizes the roles and mechanisms of GPR37 in modulating cellular physiological activities and its involvement in immune responses, stress reactions, and neuroprotection. It aims to enhance the understanding of how GPR37 modulates brain function and facilitate the identification of novel therapeutic targets or strategies for related diseases. [ABSTRACT FROM AUTHOR]

Retinoic acid receptor B2 (RARẞ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARẞ agonist drug, C286, that modulates neuron- glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-a9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve- injured rats. We also found that other clinically available retinoids, that are not RARẞ specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARẞ specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARẞ2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Osteolytic bone cancer pain is a primary concern for cancer patients with bone metastasis, and current therapies offer inadequate pain relief. The present study demonstrates that activation of the G protein-coupled receptor 37 (GPR37) by neuroprotectin D1 (NPD1) or artesunate (ARU) alleviates both acute and persistent pain in multiple mouse models of bone cancer. GPR37 agonists also protect against cancer-induced bone destruction. Mechanistically, NPD1 or ARU binding to GPR37 in macrophages promotes the release of IL-10, which further inhibits cancer-induced osteoclastogenesis. Moreover, direct activation of GPR37 in dorsal root ganglion (DRG) neurons and the spinal dorsal horn reduces action potential firing and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), thereby suppressing cancer-induced neuronal hyperexcitability. Importantly, the analgesic and protective effects of NPD1 and ARU are abolished in Gpr37 -/- mice, and β-arrestin 2 is identified as a key mediator in IL-10 release and neuronal inhibition. In patients with bone metastases, plasma levels of endogenous NPD1 are negatively correlated with both pain intensity and the bone resorption marker CTX-I. Collectively, these findings highlight GPR37 activation as a potential therapeutic strategy for alleviating bone cancer pain through direct and synergistic inhibition of osteoclastogenesis and neuronal hyperexcitability., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with increasing prevalence. Over 1,000 risk genes have now been implicated in ASD, suggesting diverse etiology. However, the diagnostic criteria for the disorder still comprise two major behavioral domains - deficits in social communication and interaction, and the presence of restricted and repetitive patterns of behavior (RRBs). The RRBs associated with ASD include both stereotyped repetitive movements and other motor manifestations including changes in gait, balance, coordination, and motor skill learning. In recent years, the striatum, the primary input center of the basal ganglia, has been implicated in these ASD-associated motor behaviors, due to the striatum's role in action selection, motor learning, and habit formation. Numerous mouse models with mutations in ASD risk genes have been developed and shown to have alterations in ASD-relevant behaviors. One commonly used assay, the accelerating rotarod, allows for assessment of both basic motor coordination and motor skill learning. In this corticostriatal-dependent task, mice walk on a rotating rod that gradually increases in speed. In the extended version of this task, mice engage striatal-dependent learning mechanisms to optimize their motor routine and stay on the rod for longer periods. This review summarizes the findings of studies examining rotarod performance across a range of ASD mouse models, and the resulting implications for the involvement of striatal circuits in ASD-related motor behaviors. While performance in this task is not uniform across mouse models, there is a cohort of models that show increased rotarod performance. A growing number of studies suggest that this increased propensity to learn a fixed motor routine may reflect a common enhancement of corticostriatal drive across a subset of mice with mutations in ASD-risk genes. [ABSTRACT FROM AUTHOR]

A seventeen-year-old girl was referred to the emergency department with dysphagia and dyspnea due to large swelling in the floor of the mouth after 20 days of evaluation. Magnetic resonance imaging shows a well-defined sublingual mass measuring 70 mm × 74 mm × 46 mm , causing severe oral and oropharyngeal space narrowing. The surgical excision of the lesion was performed through an intraoral approach under general anesthesia. Moreover, the pathologist reported a dermoid cyst. A dermoid cyst rapidly enlarging can lead to a life-threatening condition, particularly if they grow near main upper airway structures, so their resection in golden time has an especially clinical importance. [ABSTRACT FROM AUTHOR]

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondroma (HMO), is an autosomal dominant disorder caused by pathogenic variants in exostosin‐1 or ‐2 (EXT1 or EXT2). It is characterized by the formation of multiple benign growing osteochondromas (exostoses) that most commonly affect the long bones; however, it may also occur throughout the body. Although many of these lesions are clinically asymptomatic, some can lead to chronic pain and skeletal deformities and interfere with adjacent neurovascular structures. Here, we report two unrelated probands that presented with a clinical and molecular diagnosis of HME with venous malformation, a clinical feature not previously reported in individuals with HME. [ABSTRACT FROM AUTHOR]

Inflammation often accompanies preterm birth and contributes to poor neurodevelopment in preterm infants. The purpose of this study was to describe postnatal cytokine trajectories among non-infected very preterm infants during the first weeks of life. Blood samples for cytokine analysis were collected weekly from infants born between 28 and 31 weeks post-menstrual age. We used linear mixed models to calculate slopes for each cytokine and allowed the slopes to differ by infant biological sex and post-menstrual age at birth. Levels of interleukin-6, interleukin-8, and interleukin-1 receptor antagonist decreased, on average, during the neonatal period. Monocyte chemoattractant protein-1 levels increased over time, and tumor necrosis factor-alpha levels were stable. Interleukin-6 and interleukin-8 slopes differed by post-menstrual age at birth but were unaffected by infant sex. Knowledge of average cytokine trajectories may be useful in identifying infants with unresolving inflammation that increases their risk for poor neurodevelopment. [ABSTRACT FROM AUTHOR]

Inflammation is considered a fundamental process accompanying physiological human birth, also playing a role in perinatal pathologies. The goal of the study was to assess the concentrations of inflammatory molecules with respect to the mode of delivery and dynamics of inflammatory molecules in neonatal samples in the first 48–72 hours of life. The concentrations of inflammatory cytokines were measured using the Luminex®xMAP multi-analyte profiling platform in cord blood and peripheral neonatal blood. Study groups included newborns delivered spontaneously (spontaneous group) and via elective caesarean section (elective group). Cord blood concentrations of interleukin 6 (IL-6) and procalcitonin were significantly higher (P < 0.0001) in the spontaneous group compared to the elective group. Neonatal blood concentrations of tumour necrosis factor (TNF) from the elective group were significantly higher compared to the spontaneous group (P = 0.0077). The concentrations of procalcitonin and TNF significantly increased within the first 48 to 72 hours following either mode of delivery. IL-6 and IL-18 were significantly higher in neonatal compared to umbilical cord blood in the elective group only, while the increase in the spontaneous group did not reach statistical significance. The concentrations of IL-1α, IL-1β, IL-17A and IL-22 did not show significant differences between the spontaneous and elective groups as well as between umbilical cord and neonatal blood. Our findings show physiological differences in the levels of inflammatory molecules following spontaneous vaginal delivery and elective caesarean section. The results can be used as baseline values for the research of various pathologies in newborns. [ABSTRACT FROM AUTHOR]

Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms., (© 2024 The Authors. BioEssays published by Wiley Periodicals LLC.)

Objective: To investigate the therapeutic effect and influencing factors of perampanel (PER) on electrical status epilepticus during sleep (ESES). Methods: We retrospectively analyzed the clinical data of pediatric patients with focal epilepsy and ESES who were treated at the Epilepsy Center of Shengjing Hospital of China Medical University between January 2016 and March 2022. Changes in the spike wave index (SWI) after 24 weeks of PER add-on treatment were compared. Kaplan-Meier survival analysis, the log-rank test and multivariate Cox regression analysis were performed. Results: A total of 54 pediatric patients met the inclusion criteria, including 33 males and 21 females. The mean age at the diagnosis of epilepsy was 6.41 ± 2.14 years and at ESES diagnosis was 7.58 ± 2.40 years. The mean ESES duration before add-on PER was 25.31 ± 15.12 months. The mean age of the patients at add-on PER initiation was 9.69 ± 2.12 years. The ESES resolved in 29 children after 6 months of PER add-on treatment, and the response rate was 53.7%. Univariate analysis with the log-rank test showed that the therapeutic effect of PER differed according to the age at ESES diagnosis and ESES duration before add-on PER treatment. Multivariate Cox regression analysis showed that only ESES duration before PER administration was a risk factor for PER treatment failure, and the other factors had no effect on the therapeutic effect. Conclusion: PER add-on treatment has a good therapeutic effect on ESES and can be used as an alternative to corticosteroid and benzodiazepines. The therapeutic effect of PER add-on treatment was not related to the dose. A longer ESES duration results in a worse therapeutic effect. Therefore, more aggressive treatment measures should be implemented for ESES. [ABSTRACT FROM AUTHOR]

Background: The link between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) has been largely demonstrated. Some scholars have hypothesized that self-regulation mechanisms might play a key role in explaining this association. Objective(s): The current study tested the hypothesis that retrospective childhood ADHD symptoms might lead to more severe SUDs and this association should be mediated by current self-ratings of behavioral disinhibition, inattention, and emotional dysregulation among 204 treatment-seeking adults (male: 67.3%; female: 32.7%) with a primary diagnosis of alcohol use disorder and other SUDs. Methods: The mediational model was estimated through self-report measures of childhood ADHD symptoms (independent variable; WURS), current self-regulation mechanisms (mediators)—behavioral disinhibition (BIS-11 motor subscale), difficulties with attention regulation (MAAS) and emotion regulation (DERS)—and severity of SUDs (dependent variable; SPQ alcohol, illicit and prescribed drugs). Results: The analysis showed that alterations in the self-regulation system fully mediated the association between the severity of childhood ADHD symptoms and SUDs in adulthood. Behavioral disinhibition and difficulties in attention regulation were the most representative alterations in self-regulation processes that explained this association. Conclusions: These findings suggest it is useful to implement several therapeutic approaches (e.g. behavioral, mindfulness-based, and pharmacological) to increase the self-regulation abilities of children and adolescents with ADHD in order to reduce the probability of SUD onset in adulthood. However, future longitudinal neuroimaging and neuropsychological studies are needed to further support the role of self-regulation mechanisms in explaining the prospective association between childhood ADHD symptoms and SUDs in adulthood. [ABSTRACT FROM AUTHOR]

Purpose: To expand the mutation spectrum of patients with familial exudative vitreoretinopathy (FEVR) disease. Participants: 74 probands (53 families and 21 sporadic probands) with familial exudative vitreoretinopathy (FEVR) disease and their available family members (n = 188) were recruited for sequencing. Methods: Panel‐based targeted screening was performed on all subjects. Before sanger sequencing, variants of LRP5, NDP, FZD4, TSPAN12, ZNF408, KIF11, RCBTB1, JAG1, and CTNNA1 genes were verified by a series of bioinformatics tools and genotype–phenotype co‐segregation analysis. Results: 40.54% (30/74) of the probands were sighted to possess at least one etiological mutation of the nine FEVR‐causative genes. The etiological mutation detection rate was 37.74% (20/53) in family‐attainable probands while 47.62% (10/21) in sporadic cases. The diagnosis rate of patients in the early‐onset subgroup (≤5 years old, 45.4%) is higher than that of the children or adolescence‐onset subgroup (6–16 years old, 42.1%) and the late‐onset subgroup (≥17 years old, 39.4%). A total of 36 etiological mutations were identified in this study, comprising 26 novel mutations and 10 reported mutations. LRP5 was the most prevalent mutant gene among the 36 mutation types with a percentage of 41.67% (15/36). Followed by FZD4 (10/36, 27.78%), TSPAN12 (5/36, 13.89%), NDP (4/36, 11.11%), KIF11 (1/36, 2.78%), and RCBTB1 (1/36, 2.78%). Among these mutations, 63.89% (23/36) were missense mutations, 25.00% (9/36) were frameshift mutations, 5.56% (2/36) were splicing mutations, 5.56% (2/36) were nonsense mutations. Moreover, the clinical pathogenicity of these variants was defined according to American College of Medical Genetics (ACMG) and genomics guidelines: 41.67% (15/36) were likely pathogenic variants, 27.78% (10/36) pathogenic variants, 30.55% (11/36) variants of uncertain significance. No etiological mutations discovered in the ZNF408, JAG1, and CTNNA1 genes in this FEVR cohort. Conclusions: We systematically screened nine FEVR disease‐associated genes in a cohort of 74 Chinese probands with FEVR disease. With a detection rate of 40.54%, 36 etiological mutations of six genes were authenticated in 30 probands, including 26 novel mutations and 10 reported mutations. The most prevalent mutated gene is LRP5, followed by FZD4, TSPAN12, NDP, KIF11, and RCBTB1. In total, a de novo mutation was confirmed. Our study significantly clarified the mutation spectrum of variants bounded up to FEVR disease. [ABSTRACT FROM AUTHOR]

The Hedgehog signaling pathway is one of the fundamental pathways required for development and regulation of postnatal regeneration in a variety of tissues. The pathway has also been associated with cancers since the identification of a mutation in one of its components, PTCH, as the cause of Basal Cell Nevus Syndrome, which is associated with several cancers. Our understanding of the pathway in tumorigenesis has expanded greatly since that initial discovery over two decades ago. The pathway has tumor-suppressive and oncogenic functions depending on the context of the cancer. Furthermore, noncanonical activation of GLI transcription factors has been reported in a number of tumor types. Here, we review the roles of canonical Hedgehog signaling pathway and noncanonical GLI activation in cancers, particularly epithelial cancers, and discuss an emerging concept of the distinct outcomes that these modes have on cancer initiation and progression. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome is one of the most well‐known mitochondrial diseases, with most cases attributed to m.3243A>G. MELAS syndrome patients typically present in the first two decades of life with a broad, multi‐systemic phenotype that predominantly features neurological manifestations––stroke‐like episodes. However, marked phenotypic variability has been observed among paediatric patients, creating a clinical challenge and delaying diagnoses. Methods: A literature review of paediatric MELAS syndrome patients and a retrospective analysis in a UK tertiary paediatric neurology centre were performed. Results: Three children were included in this case series. All patients presented with seizures and had MRI changes not confined to a single vascular territory. Blood heteroplasmy varied considerably, and one patient required a muscle biopsy. Based on a literature review of 114 patients, the mean age of presentation is 8.1 years and seizures are the most prevalent manifestation of stroke‐like episodes. Heteroplasmy is higher in a tissue other than blood in most cases. Conclusion: The threshold for investigating MELAS syndrome in children with suspicious neurological symptoms should be low. If blood m.3243A>G analysis is negative, yet clinical suspicion remains high, invasive testing or further interrogation of the mitochondrial genome should be considered. [ABSTRACT FROM AUTHOR]

Mitochondria are an autonomous organelle that plays a crucial role in the metabolic aspects of a cell. Cortical spreading depression (CSD) and fluctuations in the cerebral blood flow have for long been mechanisms underlying migraine. It is a neurovascular disorder with a unilateral manifestation of disturbing, throbbing and pulsating head pain. Migraine affects 2.6% and 21.7% of the general population and is the major cause of partial disability in the age group 15–49. Higher mutation rates, imbalance in concentration of physiologically relevant molecules and oxidative stress biomarkers have been the main themes of discussion in determining the role of mitochondrial disability in migraine. The correlation of migraine with other disorders like hemiplegic migraine; mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes [MELAS]; tension‐type headache (TTH); cyclic vomiting syndrome (CVS), ischaemic stroke; and hypertension has helped in the assessment of the physiological and morphogenetic basis of migraine. Here, we have reviewed the different nuances of mitochondrial dysfunction and migraine. The different mtDNA polymorphisms that can affect the generation and transmission of nerve impulse has been highlighted and supported with research findings. In addition to this, the genetic basis of migraine pathogenesis as a consequence of mutations in nuclear DNA that can, in turn, affect the synthesis of defective mitochondrial proteins is discussed along with a brief overview of epigenetic profile. This review gives an overview of the pathophysiology of migraine and explores mitochondrial dysfunction as a potential underlying mechanism. Also, therapeutic supplements for managing migraine have been discussed at different junctures in this paper. [ABSTRACT FROM AUTHOR]

Exosomes, nanovesicles secreted by all cells, carry out intercellular communication by transmitting biologically active cargo comprising DNA, RNA, and proteins. These biomolecules reflect the status of their parent cells and can be altered by pathological conditions. Therefore, the researchers have been investigating differential sequences and quantities of DNA associated with exosomes as valuable biomarkers of diseases. Exosomes carry different types of DNA molecules, including genomic, cytoplasmic, and mitochondrial (mtDNA). The mtDNA aberrations are reported to be a hallmark of diseases involving oxidative stress, such as cancer and neurodegenerative diseases. Establishing robust in vitro models comprising appropriate cell lineages is the first step towards investigating disease-specific anomalies and testing therapeutics. Induced pluripotent stem (iPS) cells from patients with diseases have been used for this purpose since they can differentiate into various cells. The current study investigated mtDNA aberrations in exosomes secreted by primary cancer cells and neural stem cells (NSCs) differentiated from iPS cells. The primary cancer cells were isolated from surgically removed glioblastoma multiforme (GBM) tissue, and the iPS cells were produced from control and Alzheimer's disease (AD) subjects' B lymphocytes. We detected aberrations in mtDNA associated with exosomes secreted from GBM cells but not from the NSCs. This result indicates that the cells may not secrete exosomes carrying mtDNA aberration without exposure to a pathological condition. Thus, we may need to consider this fact when we use iPS cell-derived cells as an in vitro disease model. [ABSTRACT FROM AUTHOR]

The evolution of humans brought about a co-occurring evolution of the human brain, which is far larger and more complex than that of many other organisms. The brain has evolved characteristically in humans in many respects, including macro-and micro-anatomical changes in the brain structure, changes in gene expression, and cell populations and ratios. These characteristics are essential for the execution of higher functions, such as sociality, language, and cognition, which express humanity, and are thought to have been acquired over evolutionary time. However, with the acquisition of higher functions also comes the risk of the disease in which they fail. This review focuses on human brain evolution and neurodevelopmental disorders (NDDs) and discusses brain development, molecular evolution, and human brain evolution. Discussing the potential for the development and pathophysiology of NDDs acquired by human brain evolution will provide insights into the acquisition and breakdown of higher functions from a new perspective. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASDs) are diagnosed in 1/100 children worldwide, based on two core symptoms: deficits in social interaction and communication, and stereotyped behaviours. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors that transduce extracellular signals to convergent intracellular signalling and downstream cellular responses that are commonly dysregulated in ASD. Despite hundreds of GPCRs being expressed in the brain, only 23 are genetically associated with ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR; vasopressin V 1A and V 1B ; metabotropic glutamate mGlu 5 and mGlu 7 ; GABA B2 ; dopamine D 1 , D 2 and D 3 ; serotoninergic 5-HT 1B ; β 2 -adrenoceptor; cholinergic M 3 ; adenosine A 2A and A 3 ; angiotensin AT 2 ; cannabinoid CB 1 ; chemokine CX 3 CR1; orphan GPR37 and GPR85; and olfactory OR1C1, OR2M4, OR2T10 and OR52M1. Here, we review the therapeutic potential of these 23 GPCRs, as well as 5-HT 2A and 5-HT 7 , for ASD. For each GPCR, we discuss its genetic association, genetic and pharmacological manipulation in animal models, pharmacopoeia for core symptoms of ASD and rank them based on these factors. Among these GPCRs, we highlight D 2 , 5-HT 2A , CB 1 , OTR and V 1A as the more promising targets for ASD. We discuss that the dysregulation of GPCRs and their signalling is a convergent pathological mechanism of ASD. Their therapeutic potential has only begun as multiple GPCRs could mitigate ASD., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)