Prenatal caloric restriction reprograms endothelial transcriptional states and blood-brain barrier integrity: Implications for neurodevelopmental disorders.

In the mammalian hippocampus, synapses are either excitatory or inhibitory as defined by the presynaptic neurotransmitter (glutamate or GABA, respectively) and the specific ligand-gated ion channel receptors localized to the postsynaptic specialization. While numerous studies explore the formation of excitatory synapses, the process of inhibitory synapse formation is less understood. Using both loss- and gain-of-function approaches, our lab previously identified the class 4 Semaphorin Sema4D as a key regulator of inhibitory synaptogenesis. Here, using recombinant Sema4D protein as a tool to rapidly induce GABAergic synapse formation in cultured hippocampal neurons, we employ two-channel live imaging to identify changes to pre- and postsynaptic protein dynamics during inhibitory synapse formation. We find that Sema4D treatment promotes the mobility of presynaptic GAD65 protein assemblies while having a negligible effect on the behavior of the postsynaptic gephyrin scaffold, leading to increased colocalization of these proteins. In addition, Sema4D treatment promotes the recruitment of GABAARγ2 subunits to immature gephyrin scaffolds, suggesting that Sema4D primes these scaffolds for receptor recruitment. Surprisingly, we observe new colocalization events between existing gephyrin and GABAAR puncta, suggesting that clustering of either the gephyrin scaffold or the GABAAR is sufficient to nucleate assembly of the postsynaptic specialization. Overall our results support a model in which Sema4D signaling coordinates dynamic changes in both pre- and postsynaptic compartments to assemble inhibitory synapses on rapid timescales.Significance StatementThe assembly of new synaptic contacts requires precise coordination of specialized proteins in pre- and postsynaptic neurons. Inhibitory synapses, which suppress neuronal activity and are essential for circuit stability, contain distinct molecular components, yet the mechanisms governing their assembly remain poorly understood. We used Sema4D, a protein that rapidly induces inhibitory synapse formation, as a molecular tool to dissect how synaptic proteins on either side of the synaptic cleft are coordinated in space and time. Using live imaging we show that Sema4D acts on both pre- and postsynaptic compartments to recruit synaptic proteins with spatiotemporal precision. Together, these findings define the sequence of molecular events underlying inhibitory synapse assembly and have implications for neurodevelopmental disorders in which inhibition is disrupted.

Mitochondrial function has emerged as a critical regulator of neural differentiation, yet a comprehensive understanding of its diverse roles and temporal dynamics remains elusive. This systematic review synthesizes current evidence regarding mitochondrial contributions to neural stem cell differentiation and their implications for neurodevelopmental disorders. A systematic search was conducted across PubMed, Web of Science, and Scopus databases from inception to January 2025. Studies investigating mitochondrial properties during neural differentiation were included. Data extraction focused on temporal changes in mitochondrial function, molecular mechanisms, and pathological implications. Quality assessment was performed using modified SYRCLE criteria. Analysis of 50 studies revealed distinct temporal patterns of mitochondrial regulation during neural differentiation. Early stages (days 0-3) showed predominant mitochondrial fragmentation and elevated ROS levels, while intermediate stages (days 4-7) demonstrated a shift toward oxidative phosphorylation with increased fusion events. Late-stage differentiation (beyond day 7) exhibited mature mitochondrial networks and stable bioenergetic profiles. The key molecular mechanisms included calcium signaling, Wnt/β-catenin pathway activation, and dynamic regulation of fusion/fission proteins. Mitochondrial dysfunction was consistently associated with impaired neural differentiation across multiple neurodevelopmental disorders. Mitochondrial regulation of neural differentiation involves stage-specific changes in morphology, metabolism, and signaling functions. The identification of key molecular pathways provides promising therapeutic targets for neurodevelopmental disorders. Future research should focus on standardizing assessment methods, understanding tissue-specific regulation, and developing targeted interventions for clinical applications. These findings highlight the therapeutic potential of mitochondrial-targeted approaches in treating neurodevelopmental disorders and advancing regenerative medicine strategies.

MDGAs as synaptic suppressors with implications in neurodevelopmental disorders.

The role of tryptophan metabolism has been recognized in a wide range of physiological and pathological processes but is still only partially understood. Growing evidence highlights the importance of maintaining tryptophan homeostasis throughout life, with its disruption now linked to various neuropsychiatric conditions spanning from early life to aging. While it is increasingly evident that alterations in tryptophan metabolism have significant implications for both neurodevelopmental and neurodegenerative disorders, research has predominantly focused on the latter, leaving neurodevelopmental aspects comparatively underexplored. This review provides a comprehensive overview of both preclinical and clinical studies, highlighting the intricate relationship between tryptophan metabolism and neurodevelopment. Particular focus is given to the kynurenine pathway and gut microbiota-derived indole production, two interconnected metabolic branches with profound effects on brain maturation, plasticity, and immune regulation. Finally, we examine the pathophysiological consequences of tryptophan dysregulation in neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and Rett syndrome. We also discuss potential therapeutic strategies targeting tryptophan metabolism in these conditions.

The genetic changes driving the evolution of humans since the human-chimpanzee split have been elusive. Here, we report a promising candidate in a chromosomal region linked with neurological defects-17p13.3. We show that this 442-nucleotide sequence-human-accelerated region (HAR) 123-is a conserved neural enhancer that promotes neural progenitor cell (NPC) formation. While present in all mammals, HAR123 has rapidly evolved since humans diverged from chimpanzees. The human and chimpanzee HAR123 orthologs exhibit subtle differences in their neural developmental effects, and the human HAR123 ortholog uniquely regulates many genes involved in neural differentiation. We identified direct targets of the HAR123 enhancer and showed that HIC1 acts downstream of HAR123 to promote human NPC formation. HAR123-knockout mice exhibit a defect in cognitive flexibility and a shift in neural-glia ratio in specific regions of the hippocampus. Our study has implications for neurodevelopmental disorders, which are often accompanied by altered neural-glia ratio and have been linked with HARs.

5-mC DNA methylation is a fundamental epigenetic modification that plays a crucial role in neurodevelopment and neurological disorders. This review synthesizes the current understanding of 5-mC DNA methylation in neural system development and its implications in neurodevelopmental disorders. During normal neural development, 5-mC methylation precisely regulates neural stem cell differentiation and neuronal maturation through DNA methyltransferases (DNMTs) and methyl-CpG-binding domain (MBD) proteins. Disruption of these methylation patterns contributes to various neurodevelopmental disorders. In autism spectrum disorder (ASD), altered methylation patterns in specific genes like SHANK family and genome-wide methylation changes have been identified as potential diagnostic biomarkers. In fragile X syndrome, CGG trinucleotide repeat expansion increases methylation of the FMR1 gene promoter, leading to FMRP protein deficiency. Rett syndrome, primarily caused by MECP2 mutations, involves disrupted methylation-dependent transcriptional regulation. In epilepsy, DNA methylation abnormalities affect multiple epilepsy-related genes and may influence treatment responses to ketogenic diets. Despite these advances, the field faces significant challenges including tissue specificity issues, technical limitations in methylation detection, and therapeutic targeting difficulties. This review also discusses future perspectives, emphasizing the potential of DNA methylation as a therapeutic target and biomarker for neurodevelopmental disorders. Understanding these methylation mechanisms could lead to novel diagnostic tools and therapeutic strategies for various neurological conditions.

Large-scale effects of prenatal inflammation and early life circadian disruption in mice: Implications for neurodevelopmental disorders.

Methyl CpG binding protein 2 (MeCP2) is a chromatin-associated protein that remains enigmatic despite more than 30 years of research, primarily due to the ever-growing list of its molecular functions, and, consequently, its related pathologies. Loss of function MECP2 mutations cause the neurodevelopmental disorder Rett syndrome (RTT); in addition, dysregulation of MeCP2 expression and/ or function are involved in numerous other pathologies, but the mechanisms of MeCP2 regulation are unclear. Advancing technologies and burgeoning mechanistic theories assist our understanding of the complexity of MeCP2 but may inadvertently cloud it if not rigorously tested. Here, rather than focus on RTT, we examine relatively underexplored aspects of MeCP2, such as its dosage homeostasis at the gene and protein levels, its controversial participation in phase separation, and its overlooked role in depression and oxidative stress. All these factors may be essential to understanding the full scope of MeCP2 function in healthy and diseased states, but are relatively infrequently studied and require further criticism. The aim of this review is to discuss the esoteric facets of MeCP2 at the molecular and pathological levels and to consider to what extent they may be necessary for general MeCP2 function.

Maternal infection during pregnancy is associated with an increased risk of neurodevelopmental disorders, including depression, schizophrenia, and autism spectrum disorder. The hippocampus plays a critical role in these disorders, but the impact of maternal immune activation (MIA) on early hippocampal neuron function remains poorly understood. We investigated the effects of lipopolysaccharide-induced MIA in pregnant rats (20–80 μg/kg on gestational days 15–19) on the electrophysiological properties of hippocampal pyramidal neurons from newborn offspring. Primary neuronal cultures were prepared from the hippocampi of newborn rats and maintained for 13 days in vitro (DIV13). Whole-cell patch-clamp recordings assessed neuronal excitability parameters between DIV4-13. MIA significantly altered action potential characteristics in offspring hippocampal neurons, including: (1) increased latency time, threshold potential, and repolarization potential; (2) decreased peak potential, ascend and descend velocities; and (3) reduced spontaneous and evoked firing frequencies. These alterations suggest impaired glutamatergic neurotransmission in the hippocampus of MIA offspring, with potential sex-specific effects observed for spontaneous activity. Our findings demonstrate that MIA significantly decreases the excitability of hippocampal pyramidal neurons in newborn offspring. This reduced glutamatergic neurotransmission may contribute to the pathophysiology of neurodevelopmental disorders associated with maternal infection during pregnancy. This study provides novel insights into early neurophysiological changes following prenatal immune challenge that may inform therapeutic interventions targeting hippocampal function.

Metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor (GPCR) involved in neurotransmitter release throughout the central nervous system (CNS). Low levels of the receptor are correlated with intellectual disability, autism, repetitive behaviors, and seizures in patients with neurodevelopmental disorders (NDDs), including the disease Rett syndrome. These findings suggest that increasing mGlu7 activity may be of therapeutic benefit. In the current manuscript, we report the characterization of a novel transgenic mouse that overexpresses the human GRM7B splice variant at approximately fivefold higher levels compared to wild-type (WT) littermates. These animals exhibit a reciprocal decrease in expression of the mouse mGlu7A splice isoform, suggesting feedback regulation of receptor expression. Previous studies from our lab and others have shown that mGlu7 activation is permissive for long-term potentiation induction in the hippocampus and amygdala. Here, we identified subtle differences in agonist-modulated hippocampal field recordings in mice overexpressing mGlu7B, but no changes in theta burst-induced long-term potentiation. Our lab previously characterized behavioral phenotypes in Grm7−/− animals that were observed in other animal models of NDDs. Surprisingly, we find here that mGlu7B-overexpressing mice exhibit similar phenotypes to previously reported studies in Grm7−/− animals in repetitive behavior and cognition assays. Overall, these findings suggest that precise control of mGlu7 may be required to avoid abnormal phenotypes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12035-025-05183-y.

Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.

During postnatal brain development, maintaining a delicate balance between excitation and inhibition (E/I) is essential for the precise formation of neuronal circuits. The K+/cl- cotransporter 2 (KCC2) is instrumental in this process, and its dysregulation is implicated in various neurological disorders. This study utilized zebrafish (Danio rerio) to investigate the socio-cognitive consequences of KCC2 disruption. Through CRISPR-Cas9 technology, biallelic kcc2a knockout zebrafish larvae were generated, revealing behavioral abnormalities, including impaired social interactions and memory deficits. Molecular analyses unveiled alterations in key genes associated with the GABAergic and glutamatergic systems, potentially contributing to E/I imbalance. Additionally, KCC2 disruption influenced the expression of oxytocin and BDNF, crucial regulators of social behaviors, synaptic plasticity, and memory formation. The study also explored the therapeutic potential of KCC2 modulation using pharmaceuticals, showing the rescuing effects of CLP-290 and LIT-001 on social abnormalities. However, the selective impact of LIT-001 on social behaviors, not memory, highlights the complexity of neurobehavioral modulation. In summary, this study sheds light on the pivotal role of KCC2 in shaping socio-cognitive functions and suggests potential therapeutic avenues for KCC2-related neurological disorders.

Maternal immune activation (MIA) during pregnancy has been increasingly recognized as a critical factor in the development of neurodevelopmental disorders, with potential sex-specific impacts that are not yet fully understood. In this study, we utilized a murine model to explore the behavioral and molecular consequences of MIA induced by lipopolysaccharide (LPS) administration on embryonic day 12.5. Our findings indicate that male offspring exposed to LPS exhibited significant increases in anxiety-like and depression-like behaviors, while female offspring did not show comparable changes. Molecular analyses revealed alterations in pro-inflammatory cytokine levels and synaptic gene expression in male offspring, suggesting that these molecular disruptions may underlie the observed behavioral differences. These results emphasize the importance of considering sex as a biological variable in studies of neurodevelopmental disorders and highlight the need for further molecular investigations to understand the mechanisms driving these sex-specific outcomes. Our study contributes to the growing evidence that prenatal immune challenges play a pivotal role in the etiology of neurodevelopmental disorders and underscores the potential for sex-specific preventative approaches of MIA.

The endolysosomal framework plays an essential part in cellular homeostasis, particularly inside the neuronal setting, where it directs protein and organelle turnover. Dysfunctions in this framework are progressively ensnared in different neurodevelopmental disarranges (NDDs), showing modern roads for understanding and treating these conditions. This survey points to synthesizing current information on the part of the endolysosomal framework in neurodevelopment and its dysregulation in NDDs. It highlights hereditary transformations influencing endolysosomal proteins, modified trafficking, broken clearance instruments, and the suggestions of these disturbances for neuronal advancement and work. Furthermore, it examines later progress in understanding atomic instruments fundamental endolysosomal brokenness and diagrams rising helpful techniques focusing on these pathways. We conducted a comprehensive audit of the writing, centering on things that illustrate the association between endolysosomal brokenness and neurodevelopmental clutters. Uncommon consideration was given to hereditary considerations, cellular and atomic science inquire about, and restorative intercessions tending to endolysosomal framework disturbances. Prove underscores the basic part of the endolysosomal framework in neurodevelopment, with disturbances connected to a range of NDDs through components such as hereditary transformations in endolysosomal proteins, changed trafficking, and disabled clearance. Developing experiences into these atomic components offer unused targets for restorative mediations. Be that as it may, challenges stay in deciphering these discoveries into viable medications, requiring assistance to inquire about and a personalized medication approach. Understanding the endolysosomal system’s part in NDDs offers a promising pathway toward creating novel restorative methodologies. Future inquire about ought to use progressed hereditary and atomic apparatuses to unwind the complex exchange between endolysosomal dysfunctions and neurodevelopmental results, pointing for mediations that can moderate or turn around these conditions’ effect. Collaborative, multidisciplinary endeavors will be basic to interpret these bits of knowledge into clinical hone, with the extreme objective of making strides in the lives of people influenced by NDDs.

Thousands of long intergenic non-coding RNAs (lincRNAs) are transcribed throughout the vertebrate genome. A subset of lincRNAs enriched in developing brains have recently been found to contain cryptic open-reading frames and are speculated to encode micropeptides. However, systematic identification and functional assessment of these transcripts have been hindered by technical challenges caused by their small size. Here, we show that two putative lincRNAs (linc-mipep, also called lnc-rps25, and linc-wrb) encode micropeptides with homology to the vertebrate-specific chromatin architectural protein, Hmgn1, and demonstrate that they are required for development of vertebrate-specific brain cell types. Specifically, we show that NMDA receptor-mediated pathways are dysregulated in zebrafish lacking these micropeptides and that their loss preferentially alters the gene regulatory networks that establish cerebellar cells and oligodendrocytes - evolutionarily newer cell types that develop postnatally in humans. These findings reveal a key missing link in the evolution of vertebrate brain cell development and illustrate a genetic basis for how some neural cell types are more susceptible to chromatin disruptions, with implications for neurodevelopmental disorders and disease.

Epidemiological evidence implicates severe maternal infections as risk factors for neurodevelopmental disorders, such as ASD and schizophrenia. Accordingly, animal models mimicking infection during pregnancy, including the maternal immune activation (MIA) model, result in offspring with neurobiological, behavioral, and metabolic phenotypes relevant to human neurodevelopmental disorders. Most of these studies have been performed in rodents. We sought to better understand the molecular signatures characterizing the MIA model in an organism more closely related to humans, rhesus monkeys (Macaca mulatta), by evaluating changes in global metabolic profiles in MIA-exposed offspring. Herein, we present the global metabolome in six peripheral tissues (plasma, cerebrospinal fluid, three regions of intestinal mucosa scrapings, and feces) from 13 MIA and 10 control offspring that were confirmed to display atypical neurodevelopment, elevated immune profiles, and neuropathology. Differences in lipid, amino acid, and nucleotide metabolism discriminated these MIA and control samples, with correlations of specific metabolites to behavior scores as well as to cytokine levels in plasma, intestinal, and brain tissues. We also observed modest changes in fecal and intestinal microbial profiles, and identify differential metabolomic profiles within males and females. These findings support a connection between maternal immune activation and the metabolism, microbiota, and behavioral traits of offspring, and may further the translational applications of the MIA model and the advancement of biomarkers for neurodevelopmental disorders such as ASD or schizophrenia.

Developmental abnormalities of the cerebellum are among the most recognized structural brain malformations in human prenatal imaging. Yet reliable information regarding their cause in humans is sparse, and few outcome studies are available to inform prognosis. We know very little about human cerebellar development, in stark contrast to the wealth of knowledge from decades of research on cerebellar developmental biology of model organisms, especially mice. Recent studies show that multiple aspects of human cerebellar development significantly differ from mice and even rhesus macaques, a nonhuman primate. These discoveries challenge many current mouse-centric models of normal human cerebellar development and models regarding the pathogenesis of several neurodevelopmental phenotypes affecting the cerebellum, including Dandy-Walker malformation and medulloblastoma. Since we cannot model what we do not know, additional normative and pathological human developmental data are essential, and new models are needed.

The cellular architecture of the developing brain under physiological conditions has been widely studied over the years using rodent models ([Gotz and Huttner, 2005][1]), human fetal brains ([Polioudakis et al., 2019][2]), and, more recently, in vitro three-dimensional models of the primate and

Neurodevelopmental disorders are characterized by deficits in communication, cognition, attention, social behavior and/or motor control. Previous studies have pointed to the involvement of genes that regulate synaptic structure and function in the pathogenesis of these disorders. One such gene, GRM7, encodes the metabotropic glutamate receptor 7 (mGlu7 ), a G protein-coupled receptor that regulates presynaptic neurotransmitter release. Mutations and polymorphisms in GRM7 have been associated with neurodevelopmental disorders in clinical populations; however, limited preclinical studies have evaluated mGlu7 in the context of this specific disease class. Here, we show that the absence of mGlu7 in mice is sufficient to alter phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep. Moreover, Grm7 knockout mice exhibit an attenuated response to amphetamine. These findings provide rationale for further investigation of mGlu7 as a potential therapeutic target for neurodevelopmental disorders such as idiopathic autism, attention deficit hyperactivity disorder and Rett syndrome.