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Rate of recovery of D1 and D2 dopaminergic receptors in young vs. adult rat striatal tissue following alkylation with ethoxycarbonyl-ethoxy-dihydroquinoline (EEDQ).

The rate of recovery of D1 and D2 receptor binding sites in rat striatal tissue labeled with [3H]SCH-23390 or [3H]YM-09151-2 was followed daily after irreversible blockade of these receptors with the alkylating agent ethoxycarbonyl-ethoxy-dihydroquinoline (EEDQ). These rates were significantly higher in young post-weaning rats than in young adults (14% vs. 7% per day). The findings suggest that rates of synthesis of new D1 and D2 receptor proteins may be increased during a phase of neurodevelopment in the first postnatal month when the accumulation of both receptor types, especially of D1 receptors, is about maximal.

Alkylating Agents

Loss of sylvian fissure asymmetry in schizophrenia. A quantitative post mortem study.

The sylvian fissure is known to be one of the most asymmetric structures of the human brain. Sylvian fissure length was measured in post-mortem brains of 35 schizophrenic patients and 33 matched non psychiatric control subjects. The schizophrenics showed a significantly reduced length of the left sylvian fissure (-16%, p less than 0.0001) compared to the control subjects, while the right sylvian fissure length was unchanged. Sylvian fissure asymmetry (left/right ratio) was more reduced in male schizophrenics (-24%, p less than 0.001) than in female patients (-16%, p less than 0.03). This finding is consistent with several post-mortem and MRI studies showing left temporal lobe pathology in a significant proportion of patients and may indicate that schizophrenia is a disorder of early neurodevelopment causing impaired cerebral lateralization.

Adult

The brain stem reticular formation in schizophrenia.

Post-mortem brain tissue was obtained from four patients with schizophrenia and five controls to study cell groups in the brain stem reticular formation. Cholinergic neurons in the pedunculopontine nucleus (PPN) and lateral dorsal tegmental nucleus (LDT) were labeled using nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase histochemistry, while catecholaminergic neurons of the locus ceruleus (LC) were labeled immunocytochemically using an antibody to tyrosine hydroxylase. In schizophrenic patients, there were increased numbers of neurons in the PPN labeled by NADPH-diaphorase and reduced cell size in the LC. These results implicate the reticular formation as a possible pathophysiological site for at least some patients with schizophrenia. This also suggests that some of the deficits observed may be based on faulty neurodevelopment.

Aged

Gestational vitamin D concentration and child cognitive development: a longitudinal cohort study in the Environmental influences on Child Health Outcomes Program.

BACKGROUND: Low vitamin D concentrations are common-especially among those with darker pigmented skin-and are frequently observed during pregnancy. Given its important role in brain development, inadequate gestational vitamin D may impair child cognitive development. OBJECTIVES: We aimed to evaluate associations of gestational vitamin D concentrations with childhood cognitive scores, explore whether this relationship differs by self-reported race, and examine sensitive exposure windows within pregnancy. METHODS: This prospective cohort study included 912 mother-child dyads (37.3% Black, 52.3% White) from the Environmental influences on Child Health Outcomes program. 25-hydroxyvitamin D [25(OH)D] concentrations were measured in prenatal or cord blood collected between 4 and 42 wk gestation (median: 23 wk). Children's cognition was assessed at ages 7-12 y using the NIH Toolbox Cognition Battery. Relationships of 25(OH)D and cognitive scores were examined using mixed-effects linear models adjusted for confounders. Potential sensitive periods were explored by estimating population 25(OH)D patterns across gestation for varying levels of the cognitive outcomes. RESULTS: Mean gestational 25(OH)D was 23.8 ng/mL (SD: 10.0 ng/mL). Each 10-ng/mL increase was associated with greater overall (β: 1.11; 95% CI: 0.08, 2.14) and fluid cognition scores (β: 1.21; 95% CI: 0.07, 2.34), but not crystallized cognition. Although these associations were not significantly modified by self-reported race, associations appeared stronger in children of Black mothers (β: 2.99; 95% CI: 0.82, 5.16) than those in non-Black mothers (β: 0.43; 95% CI: -0.93, 1.78) for fluid cognition. Early pregnancy may be a critical exposure period, evidenced by the greatest divergence in the pattern of 25(OH)D during this period between the mothers of children in the 90th and those in the 10th percentiles of cognitive outcomes. CONCLUSIONS: Gestational 25(OH)D concentrations were positively associated with cognitive scores, especially in children of Black mothers. Given higher deficiency risk among Black women, vitamin D repletion before or in early pregnancy may be an important strategy for reducing racial disparities in child neurodevelopment.

Humans

Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome associated with dysregulation of GPR37 trafficking.

The endoplasmic reticulum (ER) serves as a key hub for protein homeostasis, maintaining a strict quality-control system that ensures only properly folded proteins reach their destinations, while misfolded proteins are degraded via ER-associated degradation (ERAD) or selective ER-phagy. JKAMP, which encodes an ER-resident transmembrane protein involved in ERAD, has not previously been associated with human disease. Here, we report bi-allelic loss-of-function variants in JKAMP in 14 affected individuals from 10 unrelated families presenting with a neurodevelopmental syndrome characterized by intellectual disability, developmental delay, seizures, hypotonia, microcephaly, and dysmorphic features. An in vivo zebrafish model lacking jkamp recapitulated key aspects of the human disorder, including developmental abnormalities and impaired myelin production, further corroborating its pathogenic role. Mechanistic studies identified GPR37, a brain-enriched orphan G protein-coupled receptor (GPCR) and known JKAMP interactor, as a critical downstream effector. GPR37 plays essential roles in dopaminergic signaling, inflammatory pain regulation, neuroprotection, and myelination. Loss of JKAMP resulted in defective folding and degradation of GPR37, leading to its accumulation within the ER and impaired trafficking to the plasma membrane, likely due to impaired ER quality control. These findings establish JKAMP as a previously unrecognized contributor to human neurodevelopment and uncover a pathogenic mechanism linking ER protein quality control to GPCR regulation and neurological disease.

Humans

A recurrent CCDC82 frameshift variant associated with syndromic neurodevelopmental disorder in a consanguineous Pakistani family.

BACKGROUND: Intellectual disabilities (IDs) are part of neurodevelopmental disorders (NDDs) and are genetically heterogeneous conditions characterized by impairments in cognition, learning, and adaptive functioning. Despite advances in gene discovery, many individuals, particularly those from understudied populations, remain without a molecular diagnosis. Recent reports implicate CCDC82 (HGNC: 26282) as an autosomal recessive ID gene, although the phenotypic spectrum and biological context remain incompletely defined. METHODS: Exome sequencing (ES) was performed in a consanguineous Pakistani family (PKMR06A) with four affected individuals presenting with moderate to severe ID. Variant segregation was confirmed by Sanger sequencing. In silico analyses, including pathogenicity prediction, protein structural modeling, and domain intolerance assessment, were used to evaluate the functional consequences of the identified variant. Spatiotemporal gene expression patterns were examined using bulk and single-cell human brain transcriptomic datasets. RESULTS: Clinically, affected individuals of family PKMR06A presented with early childhood global developmental delay, speech delay, hypotonia, gait abnormalities, spasticity, and mild facial dysmorphism. Genetic screening revealed a recurrent rare homozygous frameshift variant in CCDC82 (NM_024725.4): c.373del; p.(Asp125Ilefs*6), segregating with disease in all available affected individuals of the family. The identified c.373del variant was absent from the gnomAD database and was classified as pathogenic (PVS1, PM2, and PP1) based on ACMG/AMP criteria. The c.373del variant is predicted to introduce a premature termination codon, p.(Asp125Ilefs*6), leading to deletion of essential coiled-coil domains from the encoded protein, supporting a loss-of-function mechanism. In silico, transcriptomic analyses demonstrated preferential CCDC82 expression during prenatal human brain development, providing developmental context for the neurodevelopmental phenotype associated with the identified truncating variant. CONCLUSIONS: This study expands the mutational landscape of CCDC82 and provides additional clinical and molecular evidence supporting its role in autosomal recessive NDD. The findings reinforce the importance of CCDC82 in human neurodevelopment and highlight the value of genomic investigation in underrepresented populations.

Autosomal recessive

Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy.

PURPOSE: Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease. METHODS: To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants' blood and heterologous cell system. RESULTS: We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling. CONCLUSION: Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.

Humans

Prenatal pyrethroid exposure, placental gene network modules, and neonatal neurobehavior.

Prenatal pesticide exposure may adversely affect child neurodevelopment which may partly arise from impairing the placenta's vital role in fetal development. In a cohort of pregnant farmworkers from Thailand (N = 248), we examined the links between urinary metabolites of pyrethroid pesticides during pregnancy, placental gene expression networks derived from transcriptome sequencing, and newborn neurobehavior assessed using the NICU Network Neurobehavioral Scales (NNNS) at 5 weeks of age. Focusing on the 21 gene network modules in the placenta identified by Weighted Gene Co-expression Network Analysis, our analysis revealed significant associations between metabolites and nine distinct modules, and between thirteen modules and NNNS, with eight modules showing overlap. Notably, stress was negatively associated with the interferon alpha response and Myc target modules, and the interferon alpha response module was correlated positively with attention, and negatively with arousal, and quality of movement. The analysis also highlighted the early and late trimesters as critical periods for the exposures influence on placental function, with pyrethroid metabolites measured early in pregnancy significantly negatively associated with the protein secretion module, and those measured later in pregnancy negatively associated with modules related to oxidative phosphorylation (OXPHOS) and DNA repair. Additionally, the cumulative sum of 3-phenoxybenzoic acid across pregnancy was significantly negatively associated with the OXPHOS module. These findings suggest that prenatal exposure to pyrethroids may influence neonatal neurobehavior through specific placental mechanisms that impact gene expression of metabolic pathways, and these effects may be pregnancy period specific. These results offer valuable insights for future risk assessment and intervention strategies.

Prenatal Exposure Delayed Effects

Impact of the maternal microbiome on neonatal immune development.

Historically, multigenerational health and disease transmission have primarily focused on genetic inheritance. However, the discovery that beneficial microorganisms known as commensal microbiota outnumber human genes tenfold has reshaped this perspective, highlighting their critical role in maintaining homeostasis and protecting against pathogens. Unlike the human genome, commensal microbiota is not genetically inherited but is acquired anew with each generation. with initial gut colonization playing a pivotal role in shaping an infant's immune system, neurodevelopment, and long-term health, all heavily influenced by maternal factors. In this review, we examine emerging research on maternal microbial influences on the fetus beginning in utero. We provide an updated overview of the current insights into the impact of the vaginal microbiome during parturition on offspring immunity and discuss the potential long-term health implications for infants born via cesarean section. We explore the advantages and limitations of techniques designed to mitigate these effects, such as vaginal seeding and emphasize that the development of the neonatal immune system is a dynamic process influenced by maternal factors beyond birth, including the transfer of microbiota through breast milk and skin contact. Finally, we present gaps in current research and propose future research directions to deepen our understanding of the impacts of the maternal microbiome on her child. Together, these insights demonstrate how maternal influence on offspring health and immunity extends beyond genetic factors, encompassing the transmission of microbiota, which, in turn, has profound long-term implications for health and disease resilience, offering a novel perspective on intergenerational health dynamics.

Humans

Epigenome-wide placental methylation landscapes in relation to antenatal depressive symptoms.

Antenatal depressive symptoms (ADS) are common during pregnancy and are linked to adverse maternal and offspring neurodevelopmental outcomes. The placenta plays a central role in maternal-fetal communication and may function as an epigenetic sensor of maternal psychological stress. However, placental epigenetic signatures associated with ADS remain poorly understood. This study investigated epigenome-wide placental DNA methylation patterns associated with ADS in an Indian cohort. Placental samples were collected at delivery from women recruited in early pregnancy into the STRiDE cohort. Depressive symptoms were assessed at 24-28 weeks' gestation using the Patient Health Questionnaire-9 (PHQ-9). Participants were classified as controls (PHQ-9 ≤ 4; n = 53) or ADS (PHQ-9 > 4; n = 54). Genome-wide DNA methylation profiling was performed using the Illumina Infinium MethylationEPIC array. Epigenome-wide association analysis identified no CpG sites that remained statistically significant after Benjamini-Hochberg FDR correction. Top nominal CpGs showed medium-to-large effect sizes for ADS. Exploratory analyses of the top nominally associated CpGs annotated to genes including TAP2, LRCH1, SLITRK2, RASSF1 and IL3 implicated in immune regulation, cellular signalling and neurodevelopment. Gene enrichment analysis suggested the involvement of biological processes and pathways related to synaptic organization, ion transport, Hippo signalling, and thyroid hormone regulation. In conclusion, the study findings provide preliminary evidence of DNA methylation signatures linked to potential candidate genes and biological pathways that may be relevant to ADS, supporting the need for validation in larger independent cohorts and functional experimental studies.

Asian Indians

Generation of a hiPSC from a patient with an ITSN1-associated neurodevelopmental disorder spectrum carrying biallelic c.2893_2894insA (p.Tyr965Ter) genetic variant.

De novo truncating variants in ITSN1 are implicated in neurodevelopment disorders spectrum, however, biallelic variants in ITSN1 have not been previously identified. Here we present a hiPSC line generated from a patient dermal fibroblast carrying biallelic variant, c.2893_2894insA (p.Tyr965Ter). The hiPSC line expresses core stemness markers, mycoplasma free with normal karyotype and demonstrate trilineage differentiation capacity. The hiPSC line provides a valuable in-vitro model system to investigate its role in early brain development and neurodevelopmental disorders.

Humans

Is it correct to correct? Developmental milestones in 555 "normal" preterm infants compared with term infants.

To determine whether correction for preterm birth should be applied during developmental assessment, we conducted a prospective national survey of very premature infants (born at less than 32 weeks of gestation); neurodevelopment in the first 2 years was studied with the Dutch child health care developmental assessment. In 555 preterm children who had no evidence of handicap at 2 years of age, the age at which developmental milestones were reached was established. The results were compared with the results of the same assessment in Dutch children born at term. During the first year, the development of the very premature children equaled the development of normal children when full correction was applied. At 2 years of age, development was equal to or better than normal children's development without correction. We conclude that full correction for prematurity should be applied in the first year to avoid overreferral for developmental stimulation, whereas at 2 years of age correction is not necessary.

Age Factors

Neurotransmitters as neurotrophic factors: a new set of functions.

At the start of this review, factors were deemed trophic if they stimulated mitosis, permitted neural cell survival, promoted neurite sprouting and growth cone motility, or turned on a specific neuronal phenotype. The in vitro evidence from cell cultures is overwhelming that both neurotransmitters and neuropeptides can have such actions. Furthermore, the same chemical can exert several of these effects, either on the same or on different cell populations. Perhaps the most striking example is that of VIP, which can stimulate not only mitosis, but also survival and neurite sprouting of sympathetic ganglion neuroblasts (Pincus et al., 1990a,b). The in vivo data to support the in vitro experiments are starting to appear. A role for VIP in neurodevelopment is supported by in vivo studies that show behavioral deficits produced in neonatal rats by treatment with a VIP antagonist (Hill et al., 1991). The work of Shatz' laboratory (Chun et al., 1987; Ghosh et al., 1990) suggests that neuropeptide-containing neurons, transiently present, serve as guideposts for thalamocortical axons coming in to innervate specific cortical areas. Along similar lines, Wolff et al. (1979) demonstrated gamma-aminobutyric acid-accumulating glia in embryonic cortex that appeared to form axoglial synapses and suggested the possibility that gamma-aminobutyric acid released from the glia might play a role in synaptogenesis by increasing the number of postsynaptic thickenings. Meshul et al. (1987) have provided evidence that astrocytes can regulate synaptic density in the developing cerebellum. The work of Zagon and McLaughlin (1986a,b, 1987) has shown that naltrexone, an antagonist of the endogenous opioid peptides, affects both cell number and neuronal sprouting. Lauder's laboratory (Lauder et al., 1982) has shown a role for 5-HT in regulation of the proliferation of numerous cell types. These studies illustrate another important point, that neurotransmitters and neuropeptides function in communication not only between neurons, but also between neurons and glial cells, and between glial cells. Given that astrocytes can express virtually all of the neural receptors and can produce at least some of the neurotransmitters and neuropeptides, they must now be considered equal partners in the processes of intercellular communication in the nervous system, including the trophic responses. The actions of neurotransmitters and neuropeptides have to be considered in terms of a broad spectrum of actions that range from the trophic actions described in this review, to the classic transmitter actions, to potential roles in neurotoxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Is there atypical handedness in schizophrenia?

Ninety-three schizophrenic patients and 105 normal controls were tested in a single session on an 8-item repeat-administration handedness test. The schizophrenic group, in contrast to the normal controls, showed a shift in the distribution away from right-handedness, which was due to an increase in the proportion of mixed-handers. Additional analyses revealed that the increase in mixed-handedness was largely due to an increase of within-item variability in the schizophrenic group, which we refer to as ambiguous handedness. Nearly 20% of the schizophrenic patients were inconsistent on 3 or more items compared with 3.8% of the normal controls. This increased incidence of atypical handedness is discussed within the context of disorders of attention and neurodevelopment.

Adult

Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy.

SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1-2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient's phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490 .

Adolescent

Sex-specific biological aging clocks across organs and omics.

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.

Journal Article

Prenatal cell-free DNA methylome detects association with autism and maternal obesity.

Early identification of autism spectrum disorder (ASD) remains a critical challenge, particularly in utero when non-genetic factors such as maternal obesity (MO) are implicated. Here, we report results of whole-genome bisulfite sequencing of cell-free DNA (cfDNA) from third-trimester maternal plasma in a high-likelihood ASD pregnancy cohort associated with child (3 y) ASD diagnosis and/or MO. Differentially methylated regions (DMRs) between ASD and control cfDNA are strongly enriched for synaptic functions and genes previously implicated in ASD. These cfDNA ASD DMRs recapitulate those observed in ASD placenta and postmortem cortex and significantly overlap with MO DMRs. Our findings establish cfDNA methylation derived from maternal blood as a minimally invasive window into fetal brain ASD etiology, providing a framework for future mechanistic and early intervention studies. Future studies could investigate additional prenatal environmental exposures interacting with genetics during neurodevelopment.

Journal Article

Slow-to-recover brain-injured patients: rationale for treatment.

Approximately 10-20% of head injury survivors sustain extensive neurological damage and remain minimally or inconsistently responsive to stimuli for 3-6 months postinjury. These patients, designated as slow to recover (STR), may be candidates for sensory stimulation programs rather than traditional rehabilitation. Medical and insurance personnel have resisted referral and payment for treatment because of the lack of objective measures of progress, a theoretical basis for treatment, and evidence of treatment efficacy. A valid, reliable assessment tool has recently been developed (Western Neuro Sensory Stimulation Profile) that assesses low-level cognitive/communicative function and documents improvement in STR patients. This article addresses the theoretical rationale for treatment. Evidence from four areas--sensory deprivation, enriched environments, nervous system plasticity, and sensitive periods of neurodevelopment--suggests that sensory stimulation programs are potentially beneficial for STR patients. Speech-language pathologists are encouraged to study the recovery patterns of STR patients and to determine the efficacy of treatment strategies.

Brain