Frontiers in Molecular Neuroscience

Integrated genetic analysis reveals synaptic m6A enrichment in high-risk autism genes

2026-03-20

Shreya Doijad, Divyadharshini Sakthivel, Naveen Kumar Chandappa Gowda

Autism Spectrum Disorder (ASD), a complex neurodevelopmental condition, is characterised by reduced social and emotional expression and repetitive patterns of behaviour. The clinical observations of defects in brain development and disrupted connectivity in ASD correlate with the perturbations at the neuronal and molecular levels. While the underlying genetic basis has been extensively studied, understanding the epigenetic and epitranscriptomic regulation has only begun to unravel in the past two decades. This work aims to link the ASD clinical phenotypes to the molecular dysfunction, specifically highlighting one of the crucial mRNA modifications, N6-methyladenosine (m6A). During neuronal development, m6A, a key post-transcriptional regulator, dynamically modulates mRNA translation at synapses and is essential for maintaining synaptic plasticity. However, the mechanisms by which m6A operates at synapses in the context of ASD are poorly understood. Our work establishes connections across neuronal developmental timelines to m6A regulation and discusses the possibility of how this dysregulation may underlie the development of synaptopathies observed in ASD. By integrating previously published m6A-seq and CLIP-seq data with the SFARI gene database, we found that 41.59% (515 of 1,238 genes) of ASD risk genes are m6A-enriched. Specifically, we found 28 syndromic genes overlapping with the Synaptic m6A Epitranscriptome (SME). Here, we also shed light on the importance of m6A readers, with a focus on FMRP and YTHDF1 and their regulation at the synapse. Altogether, we suggest a model in which m6A-mediated post-transcriptional regulation influences ASD-related synaptic dysfunction.

Editorial: Neuroglycobiology

2026-03-18

Cyril Hanus, Robert G. Mealer, Liqin Zhao, Thomas S. Klarić

Coactivation of CB1 and GPR55 promotes GABA release and motor behavior at striatonigral terminals through increased dimerization induced by CB1 activation

2026-02-26

José Arturo Avalos-Fuentes, Rodolfo Sánchez-Zavaleta, Ihosvany Rodríguez Pérez, Rafael Jijón-Lorenzo, Refugio Cruz-Trujillo, María Fernanda González de la Torre, Martha Abigail Villareal Zuñiga, Benjamín Florán

CB1 and GPR55 receptors form heteromers in striatal neurons; however, the effects of these heteromers on GABA release at their terminals and their impact on motor behavior remain unknown. In this study, we investigate the presence of CB1-GPR55 heteromers on striatonigral neurons and their axon terminals, and also assess their impact on cAMP accumulation, GABA release, and motor behavior. Furthermore, we explore the effects of sequential receptor activation to examine the phenomenon of increased dimerization induced by receptor activation. A PLA assay combined with Substance P immunofluorescence demonstrated the presence of CB1-GPR55 heteromers in the dorsal striatum and substantia nigra of rats. The kainic acid lesion in the striatum leads to a decrease in PLA dots in both regions. Sequential activation of CB1R, followed by GPR55 activation (CB1→GPR55), increased cAMP accumulation and GABA release at the nigral terminals more compared to GPR55 alone activation. In contrast, simultaneous activation (CB1 + GPR55) or the reverse (GPR55→CB1) did not affect the stimulation effects of GPR55 on cAMP accumulation or GABA release. Additionally, CB1/GPR55 immunoprecipitation in synaptosomes revealed an increase during the sequential activation of CB1→GPR55. Treatments with PTx or ChTx did not alter the effects of CB1→GPR55 sequential activation on GABA release. Finally, intranigral injections of a CB1→GPR55 agonist induced more contralateral turns than GPR55 activation alone. These findings indicate that the sequential activation of CB1→GPR55 within CB1/GPR55 heteromers in striatonigral neurons enhances cAMP accumulation, GABA release, and motor behavior by increasing heteromerization via CB1 activation.

Neuroplasticity and recovery of the brain affected by substance use disorder: multilevel mechanisms and new therapeutic strategies (2020–2025)

2026-02-26

Roberto Estrada-Medina, Berle Estalin Briones-Llamoctanta, Josué Edison Turpo-Chaparro

IntroductionSubstance use disorder (SUD) is a complex neurobiological disorder characterized by the consolidation of maladaptive neuroplasticity affecting dopaminergic, glutamatergic, and neurotrophic systems, as well as cortical and subcortical networks critical for executive control, emotional regulation, and associative learning.MethodsThis systematic review was conducted in accordance with PRISMA 2020 guidelines and integrated 57 studies published between 2020 and 2025 to analyze neuroplastic mechanisms involved in vulnerability to substance use disorder and brain recovery following chronic substance exposure.ResultsThe findings revealed consistent alterations in synaptic density, BDNF/TrkB signaling, glutamatergic homeostasis, and epigenetic regulation, along with structural and functional neuroimaging changes in regions such as the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. Four core therapeutic domains for neuroplastic restoration were identified: neuromodulation approaches (including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation), compounds that promote neuroplasticity via neurotrophic signaling, epigenetic and anti-inflammatory interventions, and psychological therapies based on memory reconsolidation processes. These strategies demonstrated the capacity to normalize prefrontal activity, modulate reward networks, strengthen emotional regulation, and reduce craving.ConclusionDespite significant advances, important gaps remain, including methodological heterogeneity, scarcity of longitudinal studies, and limited clinical generalizability. Overall, the evidence suggests that recovery from substance use disorder requires multimodal interventions simultaneously targeting molecular, synaptic, and circuit-level plasticity, with growing emphasis on personalized approaches guided by neurobiological biomarkers.

Dysregulated lipid metabolism and hypomyelination in postnatal peroxisome-deficient Pex2 knockout Zellweger mice

2026-02-24

Tanja Eberhart, Khanichi N. Charles, Brenda Salumbides-Torres, Nia Price, Steven J. Fliesler, Phyllis L. Faust, Werner J. Kovacs

Peroxisomes are dynamic organelles that play a crucial role in cellular metabolism, particularly in fatty acid degradation, cholesterol homeostasis and reactive oxygen species metabolism. Their dysfunction is associated with severe neurological disorders, including Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD). In this study, we investigated the relationship between cholesterol homeostasis and myelination in postnatal peroxisome-deficient Pex2 knockout mice. We dissected the central nervous system (CNS) of 10-day-old (P10) control and Pex2−/− mice into five regions: spinal cord, brainstem, cerebellum, diencephalon and cerebral cortex. Catalase activity, a marker enzyme of peroxisomes, was significantly increased in CNS regions of Pex2−/− mice, indicating an oxidative imbalance. Proteomic analysis revealed significant alterations in peroxisomal proteins and pathways related to neurodegenerative diseases, cholesterol and fatty acid metabolism and mRNA processing. Cholesterol biosynthesis was particularly dysregulated: enzyme activities, mRNA, and protein levels were reduced in white matter regions but increased in the cerebral cortex. The elevated desmosterol levels in the brain of Pex2−/− mice indicate impaired cholesterol synthesis. Sphingolipid metabolism was also altered in the peroxisome-deficient CNS, as the protein levels of enzymes dihydroceramide desaturase 1, ceramide synthase 2, fatty acid 2-hydroxylase, and UDP-glycosyltransferase 8 were significantly decreased. Myelination was significantly reduced throughout the CNS, as evidenced by decreased activities of the myelin marker 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) and decreased mRNA and protein levels of myelin-associated proteins. The consistent decrease in ribosomal protein S6 phosphorylation in the CNS of Pex2−/− mice suggests that decreased mechanistic target of rapamycin complex 1 (mTORC1) activity contributes to hypomyelination. Gene expression analysis revealed an upregulation of pro-inflammatory cytokines and altered expression of some homeostatic and disease-associated microglial (DAM) genes. However, full DAM activation was not yet observed in Pex2−/− mice at P10. In conclusion, this study shows that systemic peroxisome deficiency leads to severe hypomyelination and dysregulation of cholesterol and fatty acid metabolism in the CNS, providing new insights into the pathophysiology of peroxisomal disorders.