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At least 19 recordsLinked to original sources
PubMed2025

Cell-type-specific dysregulation of gene expression due to Chd8 haploinsufficiency during mouse cortical development.

Disruptive variants in the chromodomain helicase CHD8 are associated with risk for autism spectrum disorder (ASD). CHD8 haploinsufficiency is hypothesized to contribute to ASD by perturbing neurodevelopmental gene expression. However, insight into cell-type-specific transcriptional effects of CHD8 haploinsufficiency remains limited. We used single-cell and single-nucleus RNA sequencing to identify dysregulated genes in the embryonic and juvenile Chd8+/- mouse cortex. Chd8 and other ASD risk-associated genes showed a convergent expression trajectory conserved between mouse and human developing cortex, increasing from progenitor zones to the cortical plate. Genes associated with neurodevelopmental disorders or involved in chromatin remodeling and neuron projection development were dysregulated in Chd8+/- embryonic radial glia. Genes implicated in synaptic activity and organization were dysregulated in Chd8+/- postnatal excitatory cortical neurons, suggesting impaired synaptogenesis. Our findings reveal complex patterns of transcriptional dysregulation due to Chd8 haploinsufficiency, potentially with distinct impacts on progenitors and maturing neurons in the excitatory neuronal lineage.

Animals↗
PubMed2026

A human-specific non-coding RNA for EFHC1, an epilepsy-associated gene, regulates neural stem cell proliferation for cortical development.

Epilepsy is a prevalent brain disorder in humans but rarely occurs naturally in other species, highlighting the potential for human-specific mechanisms in its pathogenesis, and thus, current animal models fail to recapitulate human symptoms. Comparing RNA sequencing (RNA-seq) datasets from human and mouse neural stem cells (NSCs), we identified EFHC1, a juvenile myoclonic epilepsy gene, as exhibiting a human-biased expression. EFHC1 knockdown reduced human NSC proliferation, while its overexpression in mouse embryonic brains increased cortical NSC number. Mechanistically, EFHC1 prevented endoplasmic reticulum stress, thereby reducing inflammatory activation of p38 MAPK and promoting continuous proliferation of human NSCs. We also identified pancEFHC1, a bidirectional promoter-associated non-coding RNA (pancRNA), located at the human EFHC1 promoter. Knockdown of pancEFHC1 in human NSCs increased DNA methylation to reduce EFHC1 expression, with the resulting phenotype rescued by EFHC1 overexpression. We propose that the evolutionary acquisition of pancEFHC1 has introduced a complex regulatory mechanism for EFHC1 expression that allows distinguishing it in humans.

Humans↗
PubMed2026

Asparagine Synthetase Deficiency: Neuropathological Evidence of Disrupted Cortical Development.

Asparagine synthetase deficiency (ASNSD) is a rare metabolic disease causing congenital microcephaly, severe developmental delay, and spastic quadriplegia. Although the central nervous system is severely affected, other organ systems appear unaffected by asparagine deficiency. We present an infant homozygous for the mutation c.904-1G>A in the ASNS gene, whose clinical presentation and radiological findings were typical for ASNSD. Following the patient's death at the age of 6 months, histological and immunohistochemical examination of the telencephalon revealed a vast disturbance of migration of neuronal subpopulations, consequently severe disorganization of cortical layers, and thinning of the cerebral cortex. These findings provide novel insights into disease pathogenesis and may explain the hallmark features of ASNSD, including microcephaly and epilepsy.

ASNS gene↗
PubMed1978

Neuronal migration and contact guidance in the primate telencephalon.

Over the last decade, evidence from experimental studies on neuronal migration in non-human primates has accumulated to the point where it can significantly amplify our understanding of the normal and pathological development of the human telencephalon. Systematic analysis of neuron genesis by the method of H3-thymidine autoradiography shows that in rhesus monkeys all neurons destined for the neocortex are generated near the surface of the lateral ventricle during a two-month period in the middle of gestation. Following their last cell division, young neurons migrate outwards across the cerebral wall to the developing cortical mantle, a journey that requires one to three days at early stages of neurogenesis, or more than two weeks towards the end of cortical development. From the very beginning, the basic columnar organization of the neuroepithelium favours radial migration. During later stages, when the primate telencephalic wall expands unevenly in thickness and surface area and begins to form primary fissures and cerebral promontoria, young neurons migrate to their cortical destinations in apposition to fascicles of radial glial fibres which span the full distance between the ventricular and pial surface. Furthermore, it appears that several generations of neurons all originate in the same restricted location at the ventricular surface, migrate along the same glial fascicles and consequently accumulate in the same radial cortical 'columns' in which, as a rule, somas of later generated neurons take positions external to the somas of their predecessors. It is proposed that fascicles of radial fibres (a) facilitate neuronal migration to the distant cortical plate through a complex assembly of closely-packed cells and processes that compose the developing primate telencephalon; (b) provide constraints which preserve a radial alignment of clonally related neurons in cortical columns; and (c) reproduce the mosaicism of the germinal ventricular zone at the expanded and curved cerebral surface.

Animals↗
PubMed2026

Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions.

Cortical development involves rapid progenitor expansion and cell diversification supported by tightly regulated metabolic programs, yet these programs remain largely uncharacterized in human development. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. We observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis and pentose phosphate pathway (PPP) activity during late neurogenesis. Manipulation of glucose availability in cortical organoids altered cell-type composition, increasing outer radial glia (oRG) and inhibitory neuron populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes. Ribose was sufficient to rescue radial glia (RG) gene expression changes, revert organoid cell-type composition, and restore levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating RG cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.

cell fate↗
PubMed1977

Development of cortical spreading depression and of its transition to the caudate nucleus in rats.

The development of Leão's spreading depression (SD) of electroencephalographic activity was studied in young rats by recording the accompanying slow potential changes (SPC). The propagation rate of cortical SD increased from 1.65 mm/min on Day 15 to 2.6 mm/min on Day 20; the increase of SPC amplitude and the decrease of SPC duration were less evident over the same period. The SD elicited in the caudate nucleus by microinjections of KCl did not spread to neocortex in 20- and 30-day-old rats and transition occurred in only 5% of KCl applications in 40-day-old rats. Application of a pyrrolopyrimidine derivative (BW 57-271; 5 mg/kg) increased the cortico-caudate SD transition of 100% in rats aged 20 days or older and increased the SPC amplitude in both structures. The development of SD parameters can be ascribed to dendritic growth and to the decrease of extracellular space; the cortico-caudate propagation block can be ascribed to morphological immaturity of the transitional zone.

Age Factors↗
PubMed1979

The effect of destroying the whisker follicles in mice on the sensory nerve, the thalamocortical radiation and cortical barrel development.

Electrolytic destruction of whisker follicles in mice on the day of birth has been found to cause degeneration in the sensory nerve fibres supplying the follicles. The severity of the degeneration has been assessed in animals between 2 and 20 days old by counting the total number of myelinated fibres in the maxillary nerves on both normal and lesioned sides. The degeneration is apparent after 2 days and by 20 days the nerve on the lesioned side contains only 38% of the normal fibre content. This degeneration has also been shown to involve the trigeminal root, central to the ganglion. In addition, the lesioning procedure modifies the terminations of thalamocortical fibres in the barrel region of the sensory cortex. These terminations are normally in clusters, each corresponding to a barrel, but, after lesioning the follicles, the terminals appear to be evenly distributed in layer IV and cortical barrel structures no longer develop. In postnatal mice, electrolytic destruction of whisker follicles had less effect upon maxillary nerve fibres and cortical barrels. The number of myelinated axons surviving until day 20 increased progressively with later lesioning to reach nearly 80% of the control level when lesions were made on day 10. Cortical barrels became secure earlier than the maxillary nerve, for a normal number of cortical barrels was present at day 12 when follicles were destroyed on day 4. The implications of these results for the formation of cortical barrels is discussed.

Animals↗
PubMed1975

Effects of procaine hydrochloride, diazepam, and diphenylhydantoin on seizure development in cortical and subcortical structures in rats.

Procaine HCl and diphenylhydantoin (DPH) increased the duration and propagation of epileptiform afterdischarges (ADs) produced by electrical stimulation of the amygdala in rats. Procaine and DPH also increased the rate of seizure development (kindling) produced by repeated stimulation of the amygdala. Procaine and to a limited extentDPH would themselves act as convulsants in well kindled subjects. Diazepam, on the other hand, retarded or blocked amygdaloid kindling. Diazepam trigered a high frequency (20-30 c/sec) rhtthm in the amygdala, hippocampus and preoptic area. None of these drugs had any significant effect on potentials evoked in secondary limbic sites by single electrical pulses applied to the amygdala. Also, none of these drugs had any effect on recruiting or post-tetanic potentiation (PTP) in secondary sites produced by amygdala stimulation and none of the drugs had any effect on amygdaloid AD thresholds. The effects of these drugs on the responses evoked by anterior neocortex stimulation were quite different. Diazepam had no effect on any of the characteristics of the discharge or convulsion even at twice the dose levels used for the amygdala group. Procaine and DPH, however, blocked not only the eonvulsion but the AD as well. Eighty percent of the procaine- and DPH-treated rats failed to respond with neocortical AD even at current levels as high as 2000 muA. The few cortically stimulated subjects that did respond with an AD showed a subcortical rather than a neocortical seizure response. DPH had no effect on recruiting or PTP of the transcallosal response. Both procaine and DPH produced a weak but significant increase in the amplitude of the transcallosal evoked potential, while diazepam produce a weak decrement in that response.

Amygdala↗
PubMed2025

A mouse organoid platform for modeling cerebral cortex development and cis-regulatory evolution in vitro.

Natural selection has shaped the gene regulatory networks that orchestrate cortical development, leading to structural and functional variation across mammals, but the molecular and cellular mechanisms underpinning these changes have only begun to be characterized. Here, we develop a reproducible protocol for cerebral cortex organoid generation from mouse epiblast stem cells (EpiSCs), which recapitulates the timing and cellular differentiation programs of the embryonic cortex. We generated cortical organoids from F1 hybrid EpiSCs derived from crosses between laboratory mice (C57BL/6J) and four wild-derived inbred strains spanning ∼1 M years of evolutionary divergence to comprehensively map cis-acting transcriptional regulatory variation across developing cortical cell types, using single-cell RNA sequencing (scRNA-seq). We identify hundreds of genes that exhibit dynamic allelic imbalances, providing the first insight into the developmental mechanisms underpinning changes in cortical structure and function between subspecies. These experimental methods and cellular resources represent a powerful platform for investigating gene regulation in the developing cerebral cortex.

Organoids↗
PubMed2026

Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analyzed surgical tissue from 25 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR or amplicon sequencing, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 64% (n = 16/25) of cases. Of these, five cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n = 3) or DEPDC5 (n = 2). Somatic variants were identified in 44% (n = 11/25) of cases. The genetic yield for FCDIIb was 77% of cases having a pathogenic mTOR pathway variant detected (n = 10/13), and for FCDIIa 66% (n = 6/9). High depth sequencing approaches allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 62% (n = 15/24) of the cases with ≥12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n = 9 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treatments.

Humans↗
PubMed2025

Maternal Immune Activation Disrupts Epigenomic and Functional Maturation of Cortical Excitatory Neurons.

Elevated levels of maternal pro-inflammatory cytokines during gestation can disrupt offspring neural development, increasing the risk of neurodevelopmental disorders. We studied the effects of Poly(I:C)-induced maternal immune activation (PIC-MIA) during mid-gestation on developing cortical excitatory neurons' DNA methylation and transcriptome. PIC-MIA disrupted the developmental regulation of synapse-related genes and of genes implicated in autism spectrum disorders. Genomic regions that gain or lose DNA methylation during normal development were altered following PIC-MIA, including neurodevelopmental transcription factor binding sites. The DNA methylation and transcriptional changes were consistent with a delay in excitatory neuron maturation. Whole-cell recordings showed that PIC-MIA preferentially altered the physiological development of layer 5 excitatory neurons. Taken together, present results suggest that alterations in the epigenome, through the disruption of circuit formation, may drive the long-term consequences of maternal infection during gestation.

DNA methylation↗