Abstract

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.

Introduction

Autism is a multifaceted neurodevelopmental condition that widely impacts how a person perceives, processes, and responds to the world around them. According to the reports from the National Institute of Mental Health (NIMH) and the World Health Organisation (WHO), approximately 1 in 100 children worldwide are diagnosed with Autism (Zeidan et al., 2022). Autism is described as a “spectrum” disorder because it manifests in a wide range of symptoms and levels of severity.

While Autism Spectrum Disorder (ASD) is largely heritable due to genetic predisposition, several other risk factors, including epigenetic and environmental factors, influence its development (Hallmayer et al., 2011; Cheroni et al., 2020). Symptoms of ASD majorly include social interaction impairment, delayed language development, communication difficulties and repetitive behaviours (Baird and Norbury, 2016; Berry et al., 2018). Given the considerable clinical heterogeneity among individuals with autism, the recent version of DSM-5 (Diagnostics and Statistical Manual-5) of the American Psychiatric Association has revised and expanded the diagnostic concept and criteria (Regier et al., 2013). Numerous genes have been implicated in regulating the co-occurring features of ASD, and many of these genes are found to be inherited variations (Srividhya et al., 2024). However, precise mechanisms by which these genetic alterations lead to the hallmark features of ASD remain partially understood. Along with the ASD risk genes, prenatal environmental factors like hypoxia and alterations in the neuro-epigenome also contribute to ASD (Eshraghi et al., 2018). This includes alterations in DNA methylation and transcriptome modifications (Tran et al., 2019; Tseng et al., 2022; Shafik et al., 2022).

The majority of the RNA species undergo dynamic modifications, tagged with diverse chemical moieties, called Epitranscriptomic modifications. They play a key role in maintaining cellular homeostasis by regulating RNA folding, transcription, splicing, stability, axonal transport, and translation (Wang et al., 2014; Yang et al., 2018). Among the many epitranscriptomic marks that regulate RNA fate, N6-methyladenosine (m6A) is the most abundant modification in eukaryotic RNAs, accounting for ~80% of total RNA base methylations and also the most abundant mRNA modifications in the brain and CNS (Chang et al., 2017; Chokkalla et al., 2020; Wang et al., 2021). Primarily occurring on the adenine nucleotide in the DRACH motif of the RNA sequence (D = A, G, or U; R = A or G; H = A, C, or U), its distribution varies across development and exhibits high tissue-specificity (Zhang et al., 2020).

To enable the function of m6A, it requires m6A methylation machinery, and it has 3 essential components, namely, Writers, Erasers, and Readers. The core mammalian methyltransferase complex (writers) comprises METTL3, METTL14 and WTAP, which catalyse targeted m6A deposition. This modification is reversible and can be removed by the demethylases FTO and ALKBH5. The m6A marks on the transcripts are recognised by a set of m6A-binding proteins called Readers. The functioning of m6A tags is mediated by these reader proteins, and they regulate their stability, translation, export, splicing and decay. Some of the important readers include YTH-domain containing proteins like YTHDC1/2, YTHDF1/2/3, and eIF3, FMRP and hnRNPA2/B1/C, which lack the YTH-domain.

A comprehensive study in 2012 uncovered the m6A distribution in mice brain using MERIP-Seq, and found about 13,471 m6A peaks in a total of 4,654 genes (Meyer et al., 2012). Of this, about 94.5% peaks were found in mRNAs and the remaining in several classes of ncRNAs. The mRNAs listed encoded genes involved in various brain regulatory functions such as ion channels, metabotropic receptors, transcription factors, cytoskeletal, axon guidance, synaptic plasticity, learning, and memory (Chokkalla et al., 2020; Widagdo et al., 2022). About 2,921 genes in adult mouse forebrain identified as synaptic m6A epitranscriptome (SME) are involved in the formation of tripartite synapses and in pathways seen in neurodevelopmental and psychiatric disorders (Merkurjeve al., 2018; Takumi et al., 2020). m6A modifications are detected throughout embryogenesis, with a drastic increase observed during adulthood in mice, implying that their upregulation is closely linked to neuronal maturation along with nervous system development (Meyer et al., 2012; Hess et al., 2013; Yoon et al., 2017).

The above studies indicate that m6A has emerged as a major post-transcriptional regulator, and although the functional significance of m6A in gene regulation has been extensively characterised in recent years, its specific involvement in neurodevelopmental disorders (NDDs), particularly ASD, remains insufficiently understood. To address this gap, we investigated whether a substantial proportion of ASD-associated genes are preferentially marked by m6A during early neurodevelopmental events like neurogenesis and synaptogenesis.

Autism is often referred to as a synaptopathy, as numerous ASD risk genes encode proteins that either localise to and function at synapses (Guang et al., 2018). Majorly, these proteins regulate multiple aspects of synaptic functions, such as cell adhesion and synapse formation (Neurexins, Neuroligins, Cadherins), Scaffolding (SHANK, PTEN, PSD-95), as well as maturation and protein synthesis regulators (SYNGAP1, FMR1). Modulation of local mRNA translation mechanisms in the cell body and dendritic spine contributes to synaptic abnormalities in ASD (Takumi et al., 2020). In this study, we also investigate a plausible role of m6A mRNA transcripts and suggest a model in which m6A-mediated post-transcriptional regulation influences ASD-related synaptic dysfunction.

ResultsCorrelation of m6A methylation to brain development till birth

Typically, brain development begins as early as post-conception week (PCW) 4 and developmental events, starting from neuronal proliferation till functional network development events are indicated in (Figure 1A). NDDs result from disruptions in the highly coordinated events essential for proper brain development. In ASD, there is a widespread dysregulation across multiple stages of early brain development. Numerous studies have indicated a prenatal origin of molecular and cellular defects underlying the behavioural deficits observed in ASD. This includes enlarged brain size due to a 67% increase in neuron number in the prefrontal cortex (Courchesne et al., 2011), neurogenesis and neuronal migration defects (Gilbert and Man, 2017; Courchesne et al., 2019). Furthermore, ASD risk genes substantially converge in the development of the cortex between PCW 8 to 24 (Courchesne et al., 2019). It is thought that the multigenic state of ASD arises from epigenetic effects on multiple genes.

Correlation of m6A-associated protein levels to brain development. (A) Timeline for normal brain development – from conception to infancy. (B) Heatmap representing the expression levels of m6A writers (METTL3, METTL14, METTL5, and WTAP) and erasers (FTO and ALKBH5) in hippocampus and cortex during human fetal development (PCW 12–PCW 37) as reported in Allen BrainSpan Atlas (Kang et al., 2011).

We know that neurogenesis is a dynamic process, and we were interested in understanding the nature of these proteins during neurogenesis. For this, we used data from the Allen BrainSpan Atlas, which indicates that the expression and activity of the methylation machinery vary across developmental time and brain regions. Interestingly, out of all m6A regulatory proteins, we found that METTL14 expression decreases, whereas ALKBH5 increases, in the cortex and hippocampus during embryonic development (PCW 12–PCW 37) (Figure 1B). These shifts coincide with critical periods of neurogenesis, synaptogenesis, and synaptic pruning (Yoon et al., 2017; Martinez De La Cruz et al., 2021). m6A regulation is more active during embryonic stages than in the postnatal stage, where transcripts encoding transcription factors and neurogenesis regulators are frequently methylated (Zhang et al., 2020; Shao et al., 2023). This facilitates rapid turnover and tight temporal control of gene expression. Alteration in the expression levels of these regulators modulates transcript methylation and expression patterns during brain development (Supplementary Table 1). For instance, the METTL14 knockout model exhibits impaired radial glial cell differentiation and delayed generation of cortical neuronal subtypes. This is mainly caused by the failure in m6A deposition by the methytransferase complex. These observations clearly link dysregulated m6A dynamics to neurodevelopmental disorders (NDD) (Chokkalla et al., 2020).

SFARI ASD risk genes exhibit a high prevalence of m6A-methylation

To investigate whether m6A regulates genes implicated in ASD, we integrated the SFARI Gene database (Simons Foundation Autism Research Initiative; https://gene.sfari.org/), which encompasses all the syndromic and non-syndromic ASD-implicated genes. The critical period of early brain development in humans, which includes neural proliferation and differentiation, begins as early as PCW 4 and remains highly active until PCW 20.

Previously, Yoon et al. (2017) generated a m6A-sequencing database for PCW 11 human fetal brain, providing m6A mRNA profiles during human cortical neurogenesis. Using this dataset, we quantified the proportion of SFARI genes carrying m6A modifications at PCW 11. A total of 515 out of 1,238 SFARI genes (41.59%) exhibited m6A enrichment. Next, we assessed the non-syndromic genes and found that 360 of 969 genes (38.7%) were m6A-modified. Whereas, 117 of 215 syndromic genes (54.42%) were m6A-modified (Supplementary Table 2; Figure 2A), indicating a comparatively higher prevalence of m6A tagging in syndromic ASD genes.

Prevalence of m6A-modified genes in ASD. (A) Segregation of SFARI ASD genes by their m6A modification status from human fetal brain m6A-seq data. Blue: m6A modification present on mRNA; Orange: m6A modification absent on mRNA in both syndromic and non-syndromic SFARI genes. (B) Distribution of m6A peaks on the ASD mRNA transcripts, syndromic (green) and non-syndromic (red), at PCW 11. (C) Histogram distribution of m6A ASD risk genes (syndromic) across human chromosomes. X-axis indicating chromosome number and Y-axis indicating the number of m6A-modified ASD risk genes per chromosome. (D) Classification of m6A-modified ASD risk genes (syndromic) into category 1, 2, and 3 by severity score provided by SFARI. SFARI Gene: An evolving database for the autism research community. Simons Foundation Autism Research Initiative. Available at: https://gene.sfari.org. (2026).

Further, we were interested in understanding the distribution of m6A across syndromic and non-syndromic transcripts. Analysis of m6A distribution along the mRNA transcripts suggested that all 515 genes displayed m6A within exonic regions. Additionally, 55 and 36.6% of non-syndromic genes found m6A within the 5′UTR and 3′UTR, respectively (Figure 2B). The data revealed a similar pattern between both categories. Syndromic genes showed a comparable distribution, with 60.7 and 32.5% carrying m6A in the 5′UTR and 3′UTR, respectively (Figure 2B). Interestingly, this data is consistent with a previous report, demonstrating that there is a higher m6A proportion in CDS regions of fetal tissues compared to adult tissues (Zhang et al., 2020). Thus, the observed m6A-profile has a specific role during neurogenesis and changes over the developmental timeline (Figure 2B).

To understand the distribution of syndromic m6A-modified ASD risk genes (117) across the chromosomes, we performed chromosomal distribution analysis. This revealed that the X chromosome harbours the highest number of 11 ASD genes carrying m6A methylation. Notably, key genes including FMR1, MECP2, PCDH19, and FGF13 were enriched for m6A methylation (Figure 2C). Upon further stratification of these genes according to the SFARI Gene scoring system, a substantial proportion, 59% of the m6A-modified syndromic genes, were observed within Category 1 (High Confidence) (Figure 2D). The remaining genes were distributed across Category 2 (23.1%; Strong Candidate) and Category 3 (17.9%; Suggestive Evidence) (Figure 2D).

Apart from the SFARI syndromic genes, several other non-syndromic gene candidates strongly implicated in ASD also undergo m6A modifications (Figure 2A). Some of the Category 1 genes include CTNNB1, NRXN2, NRXN1, GRIN1 and MAP1A.

Further, we looked into how CTNNB1, the gene encoding β-catenin, is identified as a Category 1 gene in the SFARI database. The m6A peaks were found in the coding sequence of its mRNA, which is regulated by m6A writer METTL3. CTNNB1 forms a transcriptional cascade with Brn2/Tbr2 prenatally and is essential for adult social behaviours (Tang et al., 2021). It has been reported that neural progenitor cells (NPCs) derived from skin fibroblasts of ASD patients showed increased cell proliferation due to dysregulated CTNNB1/Brn2 transcriptional cascade. These changes have contributed to the ASD behavioural phenotypes seen in Dishevelled mutants (Dvl1 and Dvl3) (Belinson et al., 2016).

Overall, our observations support that m6A acts as an additional post-transcriptional regulator for ASD linked genes during early development.

m6A enrichment in syndromic ASD correlates with synaptic defects

Previous reports suggest that active translation occurs at the synapse, and defects in mRNA regulation by m6A modification in ASD are not well understood. For this, we used a mouse forebrain synaptic m6A dataset (SME) (Merkurjeve al., 2018). We took a similar approach where we analysed the 117 m6A-modified ASD risk genes overlapping with the SME (Figure 3A). We identified 28 of the 117 genes within the SME dataset, suggesting these candidates may undergo m6A-mediated regulation at synapses and thereby impact synaptic function. We have summarised the role of these 28 genes and their role in neurodevelopment (Table 1). Notably, out of 28 genes, nine were predominantly nuclear, including transcription factors and chromatin remodelling proteins enriched in the nBAF and SWI/SNF complexes. As their roles within the synaptic compartment remain poorly characterised, these genes were excluded from the Gene Ontology (GO) analysis. GO enrichment analysis for cellular components revealed significant enrichment in cell junction, synapse, dendritic spine, neuron projection, alongside others (Figure 3B). This was independently validated by an alternative tool (PAN-GO), which identified the enriched cellular components (FDR p-value < 0.05) to be postsynaptic density, asymmetric synapse, neuron-to-neuron synapse, postsynaptic specialisation and synapse. The terms common to both analyses are highlighted in red in Figure 3B. All of these genes are actively expressed in the cortex during neurogenesis as well as synaptogenesis (Supplementary Table 2). The key proteins within the interaction network include CAMK2A, PTEN, SHANK3, IQSEC2, ANKS1B and SLC6A1. Mutations in these genes are associated with synaptic dysfunction and the behavioural phenotype seen in ASD and Epilepsy (Roy et al., 2020). This data strongly suggests the importance of m6A methylation on these mRNA candidates, possibly controlling the mRNA localisation or stability, impacting on synaptic function in ASD.

M6A-modified ASD high-risk genes associated with the synaptopathology. (A) Analysis of m6A-modified ASD risk genes overlapped with mouse forebrain SME, indicating ASD genes enriched for synaptic functions. (B) Gene ontology enrichment analysis performed using STRING for cellular components on 17 out of 28 genes exhibiting cytoplasmic localisation. The components highlighted in red represent terms that were also enriched in PAN-GO analysis.

Serial numberGene symbolGene nameSFARI gene scoreHuman brain development process involved1.ANKRD11Ankyrin repeat domain 111Neurogenesis, Dendritic growth2.ANKRD17*Ankyrin repeat domain 172Neuronal maturation3.ANKS1BAnkyrin repeat and sterile alpha motif domain containing 1B2Synaptogenesis, synaptic plasticity4.ARID1A*AT-rich interaction domain 1A3Neuronal proliferation and differentiation5.ATP1A3ATPase Na+/K + transporting subunit alpha 32Synaptic plasticity6.CAMK2ACalcium/calmodulin-dependent protein kinase II alpha1Dendritic spine organisation, synaptic plasticity7.CDK19Cyclin-dependent kinase 193Synaptogenesis8.CHD3*Chromodomain helicase DNA binding protein 31Neuronal migration, Axon guidance9.CHD7*Chromodomain helicase DNA binding protein 71Neural proliferation10.DNMT3A*DNA (cytosine-5-)-methyltransferase 3 alpha1Neuronal maturation, Synaptic plasticity11.EHMT1*Euchromatic histone-lysine N-methyltransferase 11Neurogenesis and neuronal maturation12.IQSEC2IQ motif and Sec7 domain 21Dendritic spine and axonal growth13.KDM3B*Lysine demethylase 3B1Neuronal maturation14.KIF5CKinesin family member 5C2Synaptogenesis, neuronal migration15.MACF1Microtubule actin crosslinking factor 13Axon guidance and neuronal migration16.NACC1Nucleus accumbens associated 11Synaptic plasticity17.NFIB*Nuclear factor I B2Neurogenesis18.NR2F1Nuclear receptor subfamily 2 group F member 12Neuronal differentiation and migration19.PPFIA3PTPRF interacting protein alpha 33Synaptogenesis and vesicle release20.PRR12Proline-rich 121Insufficient literature21.PTENPhosphatase and tensin homolog1Axon guidance, Neuronal migration22.SHANK3SH3 and multiple ankyrin repeat domains 31Neuronal maturation, synaptic plasticity23.SLC6A1Solute carrier family 6 (neurotransmitter transporter), member 11Neurotransmission24.SMARCC2*SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily c, member 21Neuronal proliferation and differentiation25.TCF20*Transcription factor 20 (AR1)1Neuronal differentiation26.TRIM8Tripartite motif containing 83Insufficient literature27.UGGT1UDP-glucose glycoprotein glucosyltransferase 13Insufficient literature28.ZFHX3*Zinc finger homeobox 33Neuronal proliferation and differentiation

m6A ASD high-risk genes associated with the synaptopathology.

*Primary nuclear localisation.

Regulation of m6A-modified high-risk ASD genes at synapse by FMRP and YTHDF1

Having identified a subset of m6A-modified ASD risk genes associated with synaptic function, we next examined whether these transcripts are recognised by m6A readers that regulate mRNA translation. We examined two well-characterised m6A readers, FMRP and YTHDF1, both known to mediate m6A-dependent regulation of mRNA translation in neurons and along axons (Zhang et al., 2018; Broix et al., 2025).

We used published CLIP-seq data for FMRP and YTHDF1 (Darnell et al., 2011; Shi et al., 2018) and assessed their overlap with the 28 m6A-modified ASD risk genes at synapse (Figure 4A). We found that 18 genes are established neuronal targets of FMRP and 13 are targets of YTHDF1 (Figure 4B). Strikingly, ten of these genes were common to both datasets, supporting the possibility of co-regulation by both reader proteins. The shared subset of synapse localised high-risk genes included CAMK2A, ANKRD11, MACF1, ATP1A3, KIF5C and NR2F1. We excluded the genes that are primarily nuclear and are not shown to localise to the cytoplasm (ANKRD17, ARID1A, SMARCC2 and TCF20). We examined the distribution of m6A across the transcript length (5’UTR, CDS, 3’UTR) for six genes using the PCW11 m6A-sequencing database. Primarily, we observed that m6A sites were enriched within the CDS region for all the genes, indicating dynamic regulation of these mature mRNA candidates during translation. As discussed previously, this observation corroborates prior data showing CDS-prevalent m6A distribution in the embryonic brain. KIF5C showed overall low m6A modification and a lack of m6A in the 3′ UTR. Whereas, ATP1A3 showed strong CDS bias (32 peaks), with comparatively fewer peaks in the 5′ UTR (6 peaks) and a complete absence in the 3′ UTR. Overall, we observed a non-uniform and gene-specific distribution of m6A peaks across these regions (Figure 4C).

Synaptic FMRP and YTHDF1 regulate m6A methylation of ASD high-risk genes. (A) Subset of overlapping m6A-modified ASD high-risk genes at synapses with known FMRP (pink) and YTHDF1 (green) targets in neurons. (B) Venn diagram illustrating the overlap among mRNA targets of FMRP (pink), mRNA targets of YTHDF1 (green), and ASD SME genes (grey). A total of 10 genes are common to all three datasets, as highlighted in the center. (C) Distribution of m6A peaks across transcript regions of six candidate mRNA targets shared by FMRP and YTHDF1.

Further, we discuss one of the candidate genes, CAMK2A, with a particular focus on its regulation and contribution to the ASD phenotype through plausible m6A regulation. CAMK2A, which encodes the α-subunit of Ca2+/calmodulin-dependent protein kinase 2, is involved in the stabilisation of dendritic protrusions, essential for synaptic plasticity and memory (Jia et al., 2014). CAMK2A was identified as a target of YTHDF1 and carries distinct m6A peaks (Shi et al., 2018). The modification occur in both exonic and intronic regions and is prominently enriched in the CDS according to the PCW 11 m6A sequencing data (9 peaks). A de novo Glu183Val (E183V) variant in CAMK2A was identified in a patient with ASD, and expression of this mutant in hippocampal neurons disrupted dendritic morphology and synaptic transmission. Homozygous E183V mutant mice showed a significant disruption in CAMK2A interactions, displayed enhanced repetitive behaviours and deficits in social interactions (Stephenson et al., 2017). In addition to this, it interacts with proteins such as Shank3, GluN2B, and mGlu5 that regulate synaptic functions and are strongly linked to ASD. Overall, these data suggested the dynamic role of m6A methylation at the synapse in both syndromic and non-syndromic candidates, and further experimental validations are needed on our observations to provide clinical relevance.

Discussion

Multiple studies have suggested that defects in ASD are linked to m6A regulation, yet no concise reports are available with an integrated approach. Here, we provide a systemic analysis of ASD high-risk genes demonstrating that the modulation of m6A modification on them would contribute to associated synaptic defects.

A total of 10,980 high-confidence m6A methylation peaks are associated with 5,049 transcripts in the human PCW 11 fetal brain. This accounts for approximately 31.4% of detected transcripts at that developmental stage (Yoon et al., 2017). Here, we demonstrate that m6A is prevalent on about 41.59% of the total SFARI dataset (515 of 1,238 genes), which includes both the syndromic and non-syndromic ASD associated genes. Additionally, a substantial proportion of Syndromic SFARI genes are m6A-regulated. The predominance of Category 1 genes among the m6A-modified set indicates that transcripts with the strongest and most reproducible genetic association to ASD are preferentially marked by m6A during early cortical development, particularly neurogenesis (Figures 2A,D). This enrichment suggests that m6A-dependent post-transcriptional regulation may be particularly relevant for high-confidence ASD risk genes, reinforcing the potential contribution of epitranscriptomic mechanisms to ASD pathogenesis. Furthermore, a notable enrichment, especially on the X chromosome, suggests m6A may disproportionately modulate transcripts that confer sex-biased vulnerability (2.8% in males and 0.65% in females) (Loomes et al., 2017) (Figure 2C). This also provides a basis for the underlying molecular mechanism in X-linked inheritance patterns observed in several syndromic forms of ASD, such as Fragile X Syndrome (FXS), Rett syndrome, and AUTSX variants.

Extending this analysis to the synaptic compartment, we identified a subset of m6A-modified ASD risk genes enriched for synaptic and postsynaptic components. Also, the majority of m6A components regulate the biological processes in the early developmental window and converge in synapse regulation pathways, indicating a crosstalk between them (Supplementary Table 1). A significant fraction of these transcripts are targets of both the m6A readers FMRP and YTHDF1 in the neurons (Supplementary Table 2). In the present study, we report a shared subset of ten high-risk genes, co-targeted by both m6A readers within the synaptic compartment, where m6A-dependent translational control could directly contribute to synaptic dysfunctions implicated in ASD (Figure 4B,C). This subset includes ANKRD11, ATP1A3, CAMK2A, KIF5C, MACF1 and NR2F1. We have excluded the four candidates which do not show reported synaptic localisation. However, evidence is emerging that supports the presence of traditionally nuclear proteins (TFs and chromatin modifiers) within axonal compartments, where they may have non-canonical functions. Therefore, some of the excluded candidates may also prove to have m6A-regulated synaptic roles. Additionally, the non-uniform m6A distribution across the six selected candidate genes highlights distinct regulatory roles for m6A sites in CDS versus UTRs (Figure 4C).

Neurons, as highly specialised and polarised cells, depend on local protein synthesis to maintain synaptic plasticity. It allows rapid change in the synaptic proteome upon stimulation by receptors such as metabotropic Glutamate Receptors (mGluRs) and N-methyl-D-Aspartate Receptors (NMDARs). Several studies have indicated an imbalance in local protein translation in ASD and FXS (Kobayashi et al., 2017; Feuge et al., 2019). In axons and at synapses, m6A methylation status on the mRNA can act as a reversible switch that can fine-tune the mRNA levels and regulate its translation in response to stimulation (Yu et al., 2018). It may have opposite effects on local translation, wherein it promotes translation in dendrites but inhibits in axons (Livneh et al., 2020). Various brain regions, including the hippocampus and prefrontal cortex, exhibit dynamic regulation of m6A upon sensory or behavioural stimuli (Walters et al., 2017). There is significant upregulation of m6A levels in a subset of transcripts in the prefrontal cortex during behavioural training in mice (Walters et al., 2017). Similarly, an increased m6A methylation was observed in the dorsal hippocampus following fear conditioning in mice (Quan et al., 2021). These studies strongly indicate that the m6A deposition is responsive to neuronal activity and behavioural experience. This consistent increase in m6A levels has been primarily attributed to decreased expression of FTO (Yen and Chen, 2021;