Migration Of Interneurons Research Articles

Both GEF domains of the autism and developmental epileptic encephalopathy-associated Trio protein are required for proper tangential migration of GABAergic interneurons

Both GEF domains of the autism and developmental epileptic encephalopathy-associated Trio protein are required for proper tangential migration of GABAergic interneurons

Dual effects of ARX poly-alanine mutations in human cortical and interneuron development.

Infantile spasms, with an incidence of 1.6 to 4.5 per 10,000 live births, are a relentless and devastating childhood epilepsy marked by severe seizures but also leads to lifelong intellectual disability. Alarmingly, up to 5% of males with this condition carry a mutation in the Aristaless-related homeobox ( ARX ) gene. Our current lack of human-specific models for developmental epilepsy, coupled with discrepancies between animal studies and human data, underscores the gap in knowledge and urgent need for innovative human models, organoids being one of the best available. Here, we used human neural organoid models, cortical organoids (CO) and ganglionic eminences organoids (GEO) which mimic cortical and interneuron development respectively, to study the consequences of PAE mutations, one of the most prevalent mutation in ARX . ARX PAE produces a decrease expression of ARX in GEOs, and an enhancement in interneuron migration. That accelerated migration is cell autonomously driven, and it can be rescued by inhibiting CXCR4. We also found that PAE mutations result in an early increase in radial glia cells and intermediate progenitor cells, followed by a subsequent loss of cortical neurons at later timepoints. Moreover, ARX expression is upregulated in COs derived from patients at 30 DIV and is associated with alterations in the expression of CDKN1C . Furthermore, ARX PAE assembloids had hyperactivity which were evident at early stages of development. With effective treatments for infantile spasms and developmental epilepsies still elusive, delving into the role of ARX PAE mutations in human brain organoids represents a pivotal step toward uncovering groundbreaking therapeutic strategies.

Dysregulation of Neuropilin-2 Expression in Inhibitory Neurons Impairs Hippocampal Circuit Development and Enhances Risk for Autism-Related Behaviors and Seizures.

Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether selective dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and enhances the risk for seizures has not been evaluated. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.

Neurocognitive, Clinical and Reelin Activity in Rehabilitation Using Neurofeedback Therapy in Patients with Schizophrenia.

Introduction: Reelin is a neuropeptide responsible for the migration and positioning of pyramidal neurons, interneurons, and Purkinje cells. In adulthood, it still supports neuroplasticity, especially dendritic spines formation and glutamatergic neurotransmission. Genetic studies have confirmed the involvement of reelin system failure in the etiopathogenesis of mental diseases, including schizophrenia. Given the role of reelin in brain cytoarchitectonics and the regularly observed reduction in its activity in prefrontal areas in cases of schizophrenia, dysfunction of the reelin pathway fits the neurodevelopmental hypothesis of schizophrenia, both as a biochemical predisposition and/or the ultimate trigger of psychosis and as a biosocial factor determining the clinical course, and finally, as a potential target for disease monitoring and treatment. Aim: The purpose of this study was to examine associations of the reelin blood level with clinical and neurocognitive parameters during an intensive, structured neurofeedback therapy of patients with schizophrenia. Methods: Thirty-seven male patients with paranoid schizophrenia were randomly divided into two groups: a group with 3-month neurofeedback as an add-on to ongoing antipsychotic treatment (NF, N18), and a control group with standard social support and antipsychotic treatment (CON, N19). The reelin serum concentration, clinical and neurocognitive tests were compared between the groups. Results: After 3-month trial (T2), the reelin serum level increased in the NF group vs. the CON group. The negative and general symptoms of PANSS (Positive and Negative Syndrome Scale) were reduced significantly more in the NF group at T2, and the d2 (d2 Sustained Attention Test) and BCIS (Beck Cognitive Insight Scale) scores improved only in the NF group. The AIS scores improved more dynamically in the NF group, but not enough to differentiate them from the CON group at T2. Conclusions: The clinical and neurocognitive improvement within the 3-month NF add-on therapy trial was associated with a significant increase of reelin serum level in schizophrenia patients.

CNSC-03. LINKING CELL FATE DETERMINATION IN THE EMBRYONIC FOREBRAIN TO PEDIATRIC HIGH-GRADE GLIOMA

Abstract BACKGROUND Pediatric high-grade gliomas are treatment resistant, usually fatal cancers encompassing diffuse midline glioma, K27-altered (DMG), and diffuse hemispheric glioma, G34R/V (DHG). Most patients harbour canonical and non-canonical mutations in histone variants H3.1 and H3.3, leading to global epigenetic dysregulation and stalled differentiation states as oligodendroglial progenitor cells (OPC) in DMG and GABAergic interneuron precursors in DHG. DLX2 is a homeobox transcription factor that directly represses OPC cell fate and promotes GABAergic interneuron cell fate and migration during early neurogenesis. Methods & Results Our lab has shown DLX2 promoter occupancy of Gad1/Gad2, and early (Olig2, Nkx2.2) and late (Myt1, Plp1) genes required for OPC differentiation in vivo. Co-expression of DLX2 with these target sequences reduces reporter gene expression in vitro, and the Dlx1/Dlx2 double knockout (DKO) mouse showed increases in Olig2, Nkx2.2, and Plp-1 expression in vivo. Transient over-expression of a Dlx2-GFP construct into murine DMG cells resulted in significant increased expression of Gad1/2 isoforms and decreased Olig2 and Nkx2.2, global restoration of H3K27me3 and loss of H3K27 acetylation, as well as a reduction in migration, invasion, and colony formation in vitro. To validate in human pHGG, we first probed an RNA-seq database containing 62 patient-derived pHGG cell lines which demonstrated an inverse correlation between DLX2 expression and OLIG1/2. Cell fate changes in DHG cell lines were evaluated by knockout of DLX2 using CRISPR/Cas9. Concurrently, OLIG1/2-expressing DMG cell lines underwent stable transfection of a DLX2-mCherry overexpression construct in conjunction with a SOX2-BFP overexpression construct, confirmed by qPCR and immunoblot. Analysis of histone H3 marks, K27M, and OPC signature genes will be compared to OPC genes from Dlx1/Dlx2 DKO mouse ganglionic eminences. CONCLUSIONS Manipulation of DLX2 in pHGG provides a model system for assessing the contribution of a homeobox factor to cell fate decisions regulating differentiation and tumorigenicity.

ARX regulates cortical interneuron differentiation and migration.

Mutations in aristaless-related homeobox ( ARX ) are associated with neurodevelopmental disorders including developmental epilepsies, intellectual disabilities, and autism spectrum disorders, with or without brain malformations. Aspects of these disorders have been linked to abnormal cortical interneuron (cIN) development and function. To further understand ARX's role in cIN development, multiple Arx mutant mouse lines were interrogated. We found that ARX is critical for controlling cIN numbers and distribution, especially, in the developing marginal zone (MZ). Single cell transcriptomics and ChIP-seq, combined with functional studies, revealed ARX directly or indirectly regulates genes involved in proliferation and the cell cycle (e.g., Bub3 , Cspr3 ), fate specification (e.g., Nkx2.1 , Maf , Mef2c ), and migration (e.g., Nkx2.1 , Lmo1 , Cxcr4 , Nrg1 , ErbB4 ). Our data suggest that the MZ stream defects primarily result from disordered cell-cell communication. Together our findings provide new insights into the mechanisms underlying cIN development and migration and how they are disrupted in several disorders.

Prenatal 1-Nitropyrene Exposure Causes Autism-Like Behavior Partially by Altering DNA Hydroxymethylation in Developing Brain.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1-nitropyrene (1-NP), a key component of motor vehicle exhaust, on autism-like behaviors in a mouse model. Three-chamber test finds that prenatal 1-NP exposure causes autism-like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1-NP-exposed weaning pups. Immunofluorescence finds that prenatal 1-NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1-NP exposure retards tangential migration of GAD67-positive interneurons and downregulates interneuron migration-related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1-NP exposure reduces hydroxymethylation of interneuron migration-related genes through inhibiting ten-eleven translocation (TET) activity in fetal forebrain. Supplement with alpha-ketoglutarate (α-KG), a cofactor of TET enzyme, reverses 1-NP-induced hypohydroxymethylation at specific sites of interneuron migration-related genes. Moreover, α-KG supplement alleviates 1-NP-induced migration retardation of interneurons in fetal forebrain. Finally, maternal α-KG supplement improves 1-NP-induced autism-like behaviors in weaning offspring. In conclusion, prenatal 1-NP exposure causes autism-like behavior partially by altering DNA hydroxymethylation of interneuron migration-related genes in developing brain.

Antisense oligonucleotide therapeutic approach for Timothy syndrome

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2–6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

Developmental trajectories of GABAergic cortical interneurons are sequentially modulated by dynamic FoxG1 expression levels

GABAergic inhibitory interneurons, originating from the embryonic ventral forebrain territories, traverse a convoluted migratory path to reach the neocortex. These interneuron precursors undergo sequential phases of tangential and radial migration before settling into specific laminae during differentiation. Here, we show that the developmental trajectory of FoxG1 expression is dynamically controlled in these interneuron precursors at critical junctures of migration. By utilizing mouse genetic strategies, we elucidate the pivotal role of precise changes in FoxG1 expression levels during interneuron specification and migration. Our findings underscore the gene dosage-dependent function of FoxG1, aligning with clinical observations of FOXG1 haploinsufficiency and duplication in syndromic forms of autism spectrum disorders. In conclusion, our results reveal the finely tuned developmental clock governing cortical interneuron development, driven by temporal dynamics and the dose-dependent actions of FoxG1.

Knockdown of Lhx6 during embryonic development results in neurophysiological alterations and behavioral deficits analogous to schizophrenia in adult rats

A decreased expression of specific interneuron subtypes, containing either the calcium binding protein parvalbumin (PV) or the neurotransmitter somatostatin (SST), are observed in the cortex and hippocampus of both patients with schizophrenia and rodent models used to study the disorder. Moreover, preclinical studies suggest that this loss of inhibitory function is a key pathological mechanism underlying the symptoms of schizophrenia. Interestingly, decreased expression of Lhx6, a key transcriptional regulator specific to the development and migration of PV and SST interneurons, is seen in human postmortem studies and following multiple developmental disruptions used to model schizophrenia preclinically. These results suggest that disruptions in interneuron development in utero may contribute to the pathology of the disorder. To recapitulate decreased Lhx6 expression during development, we used in utero electroporation to introduce an Lhx6 shRNA plasmid and knockdown Lhx6 expression in the brains of rats on gestational day 17. We then examined schizophrenia-like neurophysiological and behavioral alterations in the offspring once they reached adulthood. In utero Lhx6 knockdown resulted in increased ventral tegmental area (VTA) dopamine neuron population activity and a sex-specific increase in locomotor response to a psychotomimetic, consistent with positive symptomology of schizophrenia. However, Lhx6 knockdown had no effect on social interaction or spatial working memory, suggesting behaviors associated with negative and cognitive symptom domains were unaffected. These results suggest that knockdown of Lhx6 during development results in neurophysiological and behavioral alterations consistent with the positive symptom domain of schizophrenia in adult rats.

PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity

Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic interneurons express PAK3 as they migrate within the cortex, we here examined the role of PAK3 kinase activity in the regulation of cortical interneuron migration. During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate, where they contribute to cortical circuits. We showed that interneurons expressing a constitutively kinase active PAK3 variant (PAK3-ca) extended shorter leading processes and exhibited unstable polarity. In the upper cortical layers, they entered the cortical plate and extended radially oriented processes. In the deep cortical layers, they exhibited erratic non-processive migration movements and accumulated in the deep pathway. Pharmacological inhibition of PAK3 kinase inhibited the radial migration switch of interneurons to the cortical plate and reduced their accumulation in the deep cortical layers. Interneurons expressing a kinase dead PAK3 variant (PAK3-kd) developed branched leading processes, maintained the same polarity during migration and exhibited processive and tangentially oriented movements in the cortex. These results reveal that PAK3 kinase activity, by promoting leading process shortening and cell polarity changes, inhibits the tangential processive migration of interneurons and favors their radial re- orientation and targeting to the cortical plate. They suggest that patients expressing PAK3 variants with impaired kinase activity likely present alterations in the cortical targeting of their GABAergic interneurons.

The Roles of Cystatin B in the Brain and Pathophysiological Mechanisms of Progressive Myoclonic Epilepsy Type 1.

Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disorder, also known as Unverricht-Lundborg disease (ULD). EPM1 patients suffer from photo-sensitive seizures, stimulus-sensitive myoclonus, nocturnal myoclonic seizures, ataxia and dysarthria. In addition, cerebral ataxia and impaired GABAergic inhibition are typically present. EPM1 is caused by mutations in the Cystatin B gene (CSTB). The CSTB protein functions as an intracellular thiol protease inhibitor and inhibits Cathepsin function. It also plays a crucial role in brain development and regulates various functions in neurons beyond maintaining cellular proteostasis. These include controlling cell proliferation and differentiation, synaptic functions and protection against oxidative stress, likely through regulation of mitochondrial function. Depending on the differentiation stage and status of neurons, the protein localizes either to the cytoplasm, nucleus, lysosomes or mitochondria. Further, CSTB can also be secreted to the extracellular matrix for interneuron rearrangement and migration. In this review, we will review the various functions of CSTB in the brain and discuss the putative pathophysiological mechanism underlying EPM1.

Maternal sevoflurane exposure increases the epilepsy susceptibility of adolescent offspring by interrupting interneuron development

BackgroundExposure to general anesthesia influences neuronal functions during brain development. Recently, interneurons were found to be involved in developmental neurotoxicity by anesthetic exposure. But the underlying mechanism and long-term consequences remain elusive.MethodsPregnant mice received 2.5% sevoflurane for 6-h on gestational day 14.5. Pentylenetetrazole (PTZ)-induced seizure, anxiety- and depression-like behavior tests were performed in 30- and 60-day-old male offspring. Cortical interneurons were labeled using Rosa26-EYFP/-; Nkx2.1-Cre mice. Immunofluorescence and electrophysiology were performed to determine the cortical interneuron properties. Q-PCR and in situ hybridization (ISH) were performed for the potential mechanism, and the finding was further validated by in utero electroporation (IUE).ResultsIn this study, we found that maternal sevoflurane exposure increased epilepsy susceptibility by using pentylenetetrazole (PTZ) induced-kindling models and enhanced anxiety- and depression-like behaviors in adolescent offspring. After sevoflurane exposure, the highly ordered cortical interneuron migration was disrupted in the fetal cortex. In addition, the resting membrane potentials of fast-spiking interneurons in the sevoflurane-treated group were more hyperpolarized in adolescence accompanied by an increase in inhibitory synapses. Both q-PCR and ISH indicated that CXCL12/CXCR4 signaling pathway downregulation might be a potential mechanism under sevoflurane developmental neurotoxicity which was further confirmed by IUE and behavioral tests. Although the above effects were obvious in adolescence, they did not persist into adulthood.ConclusionsOur findings demonstrate that maternal anesthesia impairs interneuron migration through the CXCL12/CXCR4 signaling pathway, and influences the interneuron properties, leading to the increased epilepsy susceptibility in adolescent offspring. Our study provides a novel perspective on the developmental neurotoxicity of the mechanistic link between maternal use of general anesthesia and increased susceptibility to epilepsy.

Sialyltransferase Mutations Alter the Expression of Calcium-Binding Interneurons in Mice Neocortex, Hippocampus and Striatum.

Gangliosides are major glycans on vertebrate nerve cells, and their metabolic disruption results in congenital disorders with marked cognitive and motor deficits. The sialyltransferase gene St3gal2 is responsible for terminal sialylation of two prominent brain gangliosides in mammals, GD1a and GT1b. In this study, we analyzed the expression of calcium-binding interneurons in primary sensory (somatic, visual, and auditory) and motor areas of the neocortex, hippocampus, and striatum of St3gal2-null mice as well as St3gal3-null and St3gal2/3-double null. Immunohistochemistry with highly specific primary antibodies for GABA, parvalbumin, calretinin, and calbindin were used for interneuron detection. St3gal2-null mice had decreased expression of all three analyzed types of calcium-binding interneurons in all analyzed regions of the neocortex. These results implicate gangliosides GD1a and GT1b in the process of interneuron migration and maturation.

Inhibitory neuron map of sevoflurane induced neurotoxicity model in young primates.

Sevoflurane, one of the most commonly used anesthetic agents in children, may induce neuronal dysfunction and cognitive impairment. Exposure to sevoflurane might induce an imbalance between neural excitation and inhibition which could be a mechanism behind anesthesia-induced cognitive and affective dysfunctions. However, the underlying mechanisms remain unclear. In this study, we used two rhesus macaques in the control group, and one rhesus macaques in the anesthesia group. We employed single-nucleus RNA sequencing (snRNA-seq) technology to explore alterations in distinct types of inhibitory neurons involved in the long-term cognitive impairment caused by sevoflurane in young macaques. Following sevoflurane treatment, an upregulation was observed in the SST+ inhibitory neuron in the LHX6+ neighborhood in the hippocampus of rhesus macaques. This alteration might impact brain development by influencing interneuron migration and maturation. Additionally, we proposed a novel classification of inhibitory neurons, defined by CNR1 and LHX6 applicable to both humans and macaques. Our study proposed a novel classification of inhibitory neurons defined by LHX6 and CNR1, relevant in macaques and humans. We also provide evidence that sevoflurane upregulated the SST+ inhibitory neuron in the LHX6+ neighborhood in the hippocampus of rhesus macaques, which may underlie the potential neurotoxic effects induced by general anesthetics. Our results also offer a more reliable approach for studying the structure and function of the human brain.

Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment.

The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain1-3, which has been challenging to study at inaccessible stages of late gestation and early postnatal human development4. Autism spectrum disorder and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development5, but which of these NDD genes affect interneuron generation and migration, and how they mediate these effects remains unknown. We previously developed a platform to study interneuron development and migration in subpallial organoids and forebrain assembloids6. Here we integrate assembloids with CRISPR screening to investigate the involvement of 425 NDD genes in human interneuron development. The first screen aimed at interneuron generation revealed 13 candidate genes, including CSDE1 and SMAD4. We subsequently conducted an interneuron migration screen in more than 1,000 forebrain assembloids that identified 33 candidate genes, including cytoskeleton-related genes and the endoplasmic reticulum-related gene LNPK. We discovered that, during interneuron migration, the endoplasmic reticulum is displaced along the leading neuronal branch before nuclear translocation. LNPK deletion interfered with this endoplasmic reticulum displacement and resulted in abnormal migration. These results highlight the power of this CRISPR-assembloid platform to systematically map NDD genes onto human development and reveal disease mechanisms.

Interneuron odyssey: molecular mechanisms of tangential migration.

Cortical GABAergic interneurons are critical components of neural networks. They provide local and long-range inhibition and help coordinate network activities involved in various brain functions, including signal processing, learning, memory and adaptative responses. Disruption of cortical GABAergic interneuron migration thus induces profound deficits in neural network organization and function, and results in a variety of neurodevelopmental and neuropsychiatric disorders including epilepsy, intellectual disability, autism spectrum disorders and schizophrenia. It is thus of paramount importance to elucidate the specific mechanisms that govern the migration of interneurons to clarify some of the underlying disease mechanisms. GABAergic interneurons destined to populate the cortex arise from multipotent ventral progenitor cells located in the ganglionic eminences and pre-optic area. Post-mitotic interneurons exit their place of origin in the ventral forebrain and migrate dorsally using defined migratory streams to reach the cortical plate, which they enter through radial migration before dispersing to settle in their final laminar allocation. While migrating, cortical interneurons constantly change their morphology through the dynamic remodeling of actomyosin and microtubule cytoskeleton as they detect and integrate extracellular guidance cues generated by neuronal and non-neuronal sources distributed along their migratory routes. These processes ensure proper distribution of GABAergic interneurons across cortical areas and lamina, supporting the development of adequate network connectivity and brain function. This short review summarizes current knowledge on the cellular and molecular mechanisms controlling cortical GABAergic interneuron migration, with a focus on tangential migration, and addresses potential avenues for cell-based interneuron progenitor transplants in the treatment of neurodevelopmental disorders and epilepsy.

X-linked neuronal migration disorders: Gender differences and insights for genetic screening.

Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by anatomical cortical defects leading to varying degrees of neurocognitive impairment, developmental delay and seizures. Refractory epilepsy affects 15 million people worldwide, and it is thought that cortical developmental disorders are responsible for 25% of childhood cases. However, little is known about the epidemiology of these disorders, nor are their aetiologies fully understood, though many are associated with sporadic genetic mutations. In this review, we aim to highlight X-linked NMDs including lissencephaly, periventricular nodular heterotopia and polymicrogyria because of their mostly familial inheritance pattern. We focus on the most prominent genes responsible: including DCX, ARX, FLNA, FMR1, L1CAM, SRPX2, DDX3X, NSHDL, CUL4B and OFD1, outlining what is known about their prevalence among NMDs, and the underlying pathophysiology. X-linked disorders are important to recognise clinically, as females often have milder phenotypes. Consequently, there is a greater chance they survive to reproductive age and risk passing the mutations down. Effective genetic screening is important to prevent and treat these conditions, and for this, we need to know gene mutations and have a clear understanding of the function of the genes involved. This review summarises the knowledge base and provides clear direction for future work by both scientists and clinicians alike.

TempShift Reveals the Sequential Development of Human Neocortex and Skewed Developmental Timing of Down Syndrome Brains.

Development is a complex process involving precise regulation. Developmental regulation may vary in tissues and individuals, and is often altered in disorders. Currently, the regulation of developmental timing across neocortical areas and developmental changes in Down syndrome (DS) brains remain unclear. The changes in regulation are often accompanied by changes in the gene expression trajectories, which can be divided into two scenarios: (1) changes of gene expression trajectory shape that reflect changes in cell type composition or altered molecular machinery; (2) temporal shift of gene expression trajectories that indicate different regulation of developmental timing. Therefore, we developed an R package TempShift to separates these two scenarios and demonstrated that TempShift can distinguish temporal shift from different shape (DiffShape) of expression trajectories, and can accurately estimate the time difference between multiple trajectories. We applied TempShift to identify sequential gene expression across 11 neocortical areas, which suggested sequential occurrence of synapse formation and axon guidance, as well as reconstructed interneuron migration pathways within neocortex. Comparison between healthy and DS brains revealed increased microglia, shortened neuronal migration process, and delayed synaptogenesis and myelination in DS. These applications also demonstrate the potential of TempShift in understanding gene expression temporal dynamics during different biological processes.

MicroRNA-dependent regulation of gene expression in GABAergic interneurons.

Information processing within neuronal circuits relies on their proper development and a balanced interplay between principal and local inhibitory interneurons within those circuits. Gamma-aminobutyric acid (GABA)ergic inhibitory interneurons are a remarkably heterogeneous population, comprising subclasses based on their morphological, electrophysiological, and molecular features, with differential connectivity and activity patterns. microRNA (miRNA)-dependent post-transcriptional control of gene expression represents an important regulatory mechanism for neuronal development and plasticity. miRNAs are a large group of small non-coding RNAs (21-24 nucleotides) acting as negative regulators of mRNA translation and stability. However, while miRNA-dependent gene regulation in principal neurons has been described heretofore in several studies, an understanding of the role of miRNAs in inhibitory interneurons is only beginning to emerge. Recent research demonstrated that miRNAs are differentially expressed in interneuron subclasses, are vitally important for migration, maturation, and survival of interneurons during embryonic development and are crucial for cognitive function and memory formation. In this review, we discuss recent progress in understanding miRNA-dependent regulation of gene expression in interneuron development and function. We aim to shed light onto mechanisms by which miRNAs in GABAergic interneurons contribute to sculpting neuronal circuits, and how their dysregulation may underlie the emergence of numerous neurodevelopmental and neuropsychiatric disorders.