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Open AccessEditorial

Pathophysiological Mechanism of Neurodevelopmental Disorders—Overview

by Koh-ichi Nagata

Cells 2022, 11(24), 4082; https://doi.org/10.3390/cells11244082 - 16 Dec 2022

Viewed by 1013

Abstract

Technological advancements in next-generation DNA sequencing have enabled elucidation of many genetic causes of neurodevelopmental disorders (NDDs) over the last two decades [...] Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

Research

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13 pages, 9743 KiB

Open AccessArticle

Hippocampal Excitatory Synaptic Transmission and Plasticity Are Differentially Altered during Postnatal Development by Loss of the X-Linked Intellectual Disability Protein Oligophrenin-1

by Noemie Cresto, Nicolas Lebrun, Florent Dumont, Franck Letourneur, Pierre Billuart and Nathalie Rouach

Cells 2022, 11(9), 1545; https://doi.org/10.3390/cells11091545 - 05 May 2022

Cited by 5 | Viewed by 1944

Abstract

Oligophrenin-1 (OPHN1) is a Rho-GTPase-activating protein (RhoGAP), whose mutations are associated with X-linked intellectual disability (XLID). OPHN1 is enriched at the synapse in both pre- and postsynaptic compartments, where it regulates the RhoA/ROCK/MLC2 signaling pathway, playing a critical role in cytoskeleton remodeling and [...] Read more.

Oligophrenin-1 (OPHN1) is a Rho-GTPase-activating protein (RhoGAP), whose mutations are associated with X-linked intellectual disability (XLID). OPHN1 is enriched at the synapse in both pre- and postsynaptic compartments, where it regulates the RhoA/ROCK/MLC2 signaling pathway, playing a critical role in cytoskeleton remodeling and vesicle recycling. Ophn1 knockout (KO) adult mice display some behavioral deficits in multiple tasks, reminiscent of some symptoms in the human pathology. We also previously reported a reduction in dendritic spine density in the adult hippocampus of KO mice. Yet the nature of the deficits occurring in these mice during postnatal development remains elusive. Here, we show that juvenile KO mice present normal basal synaptic transmission, but altered synaptic plasticity, with a selective impairment in long-term depression, but no change in long-term potentiation. This contrasts with the functional deficits that these mice display at the adult stage, as we found that both basal synaptic transmission and long-term potentiation are reduced at later stages, due to presynaptic alterations. In addition, the number of excitatory synapses in adult is increased, suggesting some unsuccessful compensation. Altogether, these results suggest that OPHN1 function at synapses is differentially affected during maturation of the brain, which provides some therapeutic opportunities for early intervention. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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26 pages, 24241 KiB

Open AccessArticle

Altered White Matter and microRNA Expression in a Murine Model Related to Williams Syndrome Suggests That miR-34b/c Affects Brain Development via Ptpru and Dcx Modulation

by Meitar Grad, Ariel Nir, Gilad Levy, Sari Schokoroy Trangle, Guy Shapira, Noam Shomron, Yaniv Assaf and Boaz Barak

Cells 2022, 11(1), 158; https://doi.org/10.3390/cells11010158 - 04 Jan 2022

Cited by 8 | Viewed by 3568

Abstract

Williams syndrome (WS) is a multisystem neurodevelopmental disorder caused by a de novo hemizygous deletion of ~26 genes from chromosome 7q11.23, among them the general transcription factor II-I (GTF2I). By studying a novel murine model for the hypersociability phenotype associated with [...] Read more.

Williams syndrome (WS) is a multisystem neurodevelopmental disorder caused by a de novo hemizygous deletion of ~26 genes from chromosome 7q11.23, among them the general transcription factor II-I (GTF2I). By studying a novel murine model for the hypersociability phenotype associated with WS, we previously revealed surprising aberrations in myelination and cell differentiation properties in the cortices of mutant mice compared to controls. These mutant mice had selective deletion of Gtf2i in the excitatory neurons of the forebrain. Here, we applied diffusion magnetic resonance imaging and fiber tracking, which showed a reduction in the number of streamlines in limbic outputs such as the fimbria/fornix fibers and the stria terminalis, as well as the corpus callosum of these mutant mice compared to controls. Furthermore, we utilized next-generation sequencing (NGS) analysis of cortical small RNAs’ expression (RNA-Seq) levels to identify altered expression of microRNAs (miRNAs), including two from the miR-34 cluster, known to be involved in prominent processes in the developing nervous system. Luciferase reporter assay confirmed the direct binding of miR-34c-5p to the 3’UTR of PTPRU—a gene involved in neural development that was elevated in the cortices of mutant mice relative to controls. Moreover, we found an age-dependent variation in the expression levels of doublecortin (Dcx)—a verified miR-34 target. Thus, we demonstrate the substantial effect a single gene deletion can exert on miRNA regulation and brain structure, and advance our understanding and, hopefully, treatment of WS. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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20 pages, 4692 KiB

Open AccessArticle

KANPHOS: A Database of Kinase-Associated Neural Protein Phosphorylation in the Brain

by Rijwan Uddin Ahammad, Tomoki Nishioka, Junichiro Yoshimoto, Takayuki Kannon, Mutsuki Amano, Yasuhiro Funahashi, Daisuke Tsuboi, Md. Omar Faruk, Yukie Yamahashi, Kiyofumi Yamada, Taku Nagai and Kozo Kaibuchi

Cells 2022, 11(1), 47; https://doi.org/10.3390/cells11010047 - 24 Dec 2021

Cited by 8 | Viewed by 4650

Abstract

Protein phosphorylation plays critical roles in a variety of intracellular signaling pathways and physiological functions that are controlled by neurotransmitters and neuromodulators in the brain. Dysregulation of these signaling pathways has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity [...] Read more.

Protein phosphorylation plays critical roles in a variety of intracellular signaling pathways and physiological functions that are controlled by neurotransmitters and neuromodulators in the brain. Dysregulation of these signaling pathways has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia. While recent advances in mass spectrometry-based proteomics have allowed us to identify approximately 280,000 phosphorylation sites, it remains largely unknown which sites are phosphorylated by which kinases. To overcome this issue, previously, we developed methods for comprehensive screening of the target substrates of given kinases, such as PKA and Rho-kinase, upon stimulation by extracellular signals and identified many candidate substrates for specific kinases and their phosphorylation sites. Here, we developed a novel online database to provide information about the phosphorylation signals identified by our methods, as well as those previously reported in the literature. The “KANPHOS” (Kinase-Associated Neural Phospho-Signaling) database and its web portal were built based on a next-generation XooNIps neuroinformatics tool. To explore the functionality of the KANPHOS database, we obtained phosphoproteomics data for adenosine-A2A-receptor signaling and its downstream MAPK-mediated signaling in the striatum/nucleus accumbens, registered them in KANPHOS, and analyzed the related pathways. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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19 pages, 2930 KiB

Open AccessArticle

Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice

by Kun Fang, Dong Liu, Salil S. Pathak, Bowen Yang, Jin Li, Ramanujam Karthikeyan, Owen Y. Chao, Yi-Mei Yang, Victor X. Jin and Ruifeng Cao

Cells 2021, 10(12), 3314; https://doi.org/10.3390/cells10123314 - 26 Nov 2021

Cited by 10 | Viewed by 4243

Abstract

Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic [...] Read more.

Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnatal day 42, we investigated the molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8 h/8 h LD cycle, and the circadian oscillations of the clock proteins, PERIOD1 and PERIOD2, were disrupted in the suprachiasmatic nucleus and the hippocampus of these mice. By RNA-seq widespread changes were identified in the hippocampal transcriptome, which are functionally associated with neurodevelopment, translational control, and autism. By western blotting and immunostaining hyperactivation of the mTOR and MAPK signaling pathways and enhanced global protein synthesis were found in the hippocampi of SD mice. Electrophysiological recording uncovered enhanced excitatory, but attenuated inhibitory, synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes at synapses were corroborated by the immature morphology of the dendritic spines in these neurons. Lastly, autistic-like animal behavioral changes, including impaired social interaction and communication, increased repetitive behaviors, and impaired novel object recognition and location memory, were found in SD mice. Together, these results demonstrate molecular, cellular, and behavioral changes in SD mice, all of which resemble autistic-like phenotypes caused by circadian rhythm disruption. The findings highlight a critical role for circadian rhythms in neurodevelopment. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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14 pages, 2400 KiB

Open AccessArticle

Siblings with MAN1B1-CDG Showing Novel Biochemical Profiles

by Nobuhiko Okamoto, Tatsuyuki Ohto, Takashi Enokizono, Yoshinao Wada, Tomohiro Kohmoto, Issei Imoto, Yoshimi Haga, Junichi Seino and Tadashi Suzuki

Cells 2021, 10(11), 3117; https://doi.org/10.3390/cells10113117 - 10 Nov 2021

Cited by 5 | Viewed by 2151

Abstract

Congenital disorders of glycosylation (CDG), inherited metabolic diseases caused by defects in glycosylation, are characterized by a high frequency of intellectual disability (ID) and various clinical manifestations. Two siblings with ID, dysmorphic features, and epilepsy were examined using mass spectrometry of serum transferrin, [...] Read more.

Congenital disorders of glycosylation (CDG), inherited metabolic diseases caused by defects in glycosylation, are characterized by a high frequency of intellectual disability (ID) and various clinical manifestations. Two siblings with ID, dysmorphic features, and epilepsy were examined using mass spectrometry of serum transferrin, which revealed a CDG type 2 pattern. Whole-exome sequencing showed that both patients were homozygous for a novel pathogenic variant of MAN1B1 (NM_016219.4:c.1837del) inherited from their healthy parents. We conducted a HPLC analysis of sialylated N-linked glycans released from total plasma proteins and characterized the α1,2-mannosidase I activity of the lymphocyte microsome fraction. The accumulation of monosialoglycans was observed in MAN1B1-deficient patients, indicating N-glycan-processing defects. The enzymatic activity of MAN1B1 was compromised in patient-derived lymphocytes. The present patients exhibited unique manifestations including early-onset epileptic encephalopathy and cerebral infarction. They also showed coagulation abnormalities and hypertransaminasemia. Neither sibling had truncal obesity, which is one of the characteristic features of MAN1B1-CDG. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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30 pages, 3441 KiB

Open AccessArticle

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

by Cecilia Cattelani, Dominik Lesiak, Gudrun Liebscher, Isabel I. Singer, Taras Stasyk, Moritz H. Wallnöfer, Alexander M. Heberle, Corrado Corti, Michael W. Hess, Kristian Pfaller, Marcel Kwiatkowski, Peter P. Pramstaller, Andrew A. Hicks, Kathrin Thedieck, Thomas Müller, Lukas A. Huber and Mariana Eca Guimaraes de Araujo

Cells 2021, 10(10), 2711; https://doi.org/10.3390/cells10102711 - 09 Oct 2021

Cited by 7 | Viewed by 4113

Abstract

Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, [...] Read more.

Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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Review

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19 pages, 2114 KiB

Open AccessReview

Brain Organization and Human Diseases

by Tamar Sapir, Dalit Sela-Donenfeld, Maayan Karlinski and Orly Reiner

Cells 2022, 11(10), 1642; https://doi.org/10.3390/cells11101642 - 14 May 2022

Cited by 7 | Viewed by 2918

Abstract

The cortex is a highly organized structure that develops from the caudal regions of the segmented neural tube. Its spatial organization sets the stage for future functional arealization. Here, we suggest using a developmental perspective to describe and understand the etiology of common [...] Read more.

The cortex is a highly organized structure that develops from the caudal regions of the segmented neural tube. Its spatial organization sets the stage for future functional arealization. Here, we suggest using a developmental perspective to describe and understand the etiology of common cortical malformations and their manifestation in the human brain. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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47 pages, 3774 KiB

Open AccessReview

Pathophysiological Heterogeneity of the BBSOA Neurodevelopmental Syndrome

by Michele Bertacchi, Chiara Tocco, Christian P. Schaaf and Michèle Studer

Cells 2022, 11(8), 1260; https://doi.org/10.3390/cells11081260 - 08 Apr 2022

Cited by 7 | Viewed by 5216

Abstract

The formation and maturation of the human brain is regulated by highly coordinated developmental events, such as neural cell proliferation, migration and differentiation. Any impairment of these interconnected multi-factorial processes can affect brain structure and function and lead to distinctive neurodevelopmental disorders. Here, [...] Read more.

The formation and maturation of the human brain is regulated by highly coordinated developmental events, such as neural cell proliferation, migration and differentiation. Any impairment of these interconnected multi-factorial processes can affect brain structure and function and lead to distinctive neurodevelopmental disorders. Here, we review the pathophysiology of the Bosch–Boonstra–Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722; ORPHA 401777), a recently described monogenic neurodevelopmental syndrome caused by the haploinsufficiency of NR2F1 gene, a key transcriptional regulator of brain development. Although intellectual disability, developmental delay and visual impairment are arguably the most common symptoms affecting BBSOAS patients, multiple additional features are often reported, including epilepsy, autistic traits and hypotonia. The presence of specific symptoms and their variable level of severity might depend on still poorly characterized genotype–phenotype correlations. We begin with an overview of the several mutations of NR2F1 identified to date, then further focuses on the main pathological features of BBSOAS patients, providing evidence—whenever possible—for the existing genotype–phenotype correlations. On the clinical side, we lay out an up-to-date list of clinical examinations and therapeutic interventions recommended for children with BBSOAS. On the experimental side, we describe state-of-the-art in vivo and in vitro studies aiming at deciphering the role of mouse Nr2f1, in physiological conditions and in pathological contexts, underlying the BBSOAS features. Furthermore, by modeling distinct NR2F1 genetic alterations in terms of dimer formation and nuclear receptor binding efficiencies, we attempt to estimate the total amounts of functional NR2F1 acting in developing brain cells in normal and pathological conditions. Finally, using the NR2F1 gene and BBSOAS as a paradigm of monogenic rare neurodevelopmental disorder, we aim to set the path for future explorations of causative links between impaired brain development and the appearance of symptoms in human neurological syndromes. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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13 pages, 940 KiB

Open AccessFeature PaperReview

Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders

by Hidenori Ito and Koh-ichi Nagata

Cells 2022, 11(2), 303; https://doi.org/10.3390/cells11020303 - 17 Jan 2022

Cited by 4 | Viewed by 2727

Abstract

The Connector Enhancer of Kinase Suppressor of Ras-2 (CNKSR2), also known as CNK2 or MAGUIN, is a scaffolding molecule that contains functional protein binding domains: Sterile Alpha Motif (SAM) domain, Conserved Region in CNK (CRIC) domain, PSD-95/Dlg-A/ZO-1 (PDZ) domain, Pleckstrin Homology (PH) domain, [...] Read more.

The Connector Enhancer of Kinase Suppressor of Ras-2 (CNKSR2), also known as CNK2 or MAGUIN, is a scaffolding molecule that contains functional protein binding domains: Sterile Alpha Motif (SAM) domain, Conserved Region in CNK (CRIC) domain, PSD-95/Dlg-A/ZO-1 (PDZ) domain, Pleckstrin Homology (PH) domain, and C-terminal PDZ binding motif. CNKSR2 interacts with different molecules, including RAF1, ARHGAP39, and CYTH2, and regulates the Mitogen-Activated Protein Kinase (MAPK) cascade and small GTPase signaling. CNKSR2 has been reported to control the development of dendrite and dendritic spines in primary neurons. CNKSR2 is encoded by the CNKSR2 gene located in the X chromosome. CNKSR2 is now considered as a causative gene of the Houge type of X-linked syndromic mental retardation (MRXHG), an X-linked Intellectual Disability (XLID) that exhibits delayed development, intellectual disability, early-onset seizures, language delay, attention deficit, and hyperactivity. In this review, we summarized molecular features, neuronal function, and neurodevelopmental disorder-related variations of CNKSR2. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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10 pages, 909 KiB

Open AccessReview

Endosomal Recycling Defects and Neurodevelopmental Disorders

by Shinji Saitoh

Cells 2022, 11(1), 148; https://doi.org/10.3390/cells11010148 - 03 Jan 2022

Cited by 9 | Viewed by 2712

Abstract

The quality and quantity of membrane proteins are precisely and dynamically maintained through an endosomal recycling process. This endosomal recycling is executed by two protein complexes: retromer and recently identified retriever. Defects in the function of retromer or retriever cause dysregulation of many [...] Read more.

The quality and quantity of membrane proteins are precisely and dynamically maintained through an endosomal recycling process. This endosomal recycling is executed by two protein complexes: retromer and recently identified retriever. Defects in the function of retromer or retriever cause dysregulation of many membrane proteins and result in several human disorders, including neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Recently, neurodevelopmental disorders caused by pathogenic variants in genes associated with retriever were identified. This review focuses on the two recycling complexes and discuss their biological and developmental roles and the consequences of defects in endosomal recycling, especially in the nervous system. We also discuss future perspectives of a possible relationship of the dysfunction of retromer and retriever with neurodevelopmental disorders. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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12 pages, 891 KiB

Open AccessReview

AUTS2 Gene: Keys to Understanding the Pathogenesis of Neurodevelopmental Disorders

by Kei Hori, Kazumi Shimaoka and Mikio Hoshino

Cells 2022, 11(1), 11; https://doi.org/10.3390/cells11010011 - 21 Dec 2021

Cited by 19 | Viewed by 5076

Abstract

Neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASD) and intellectual disability (ID), are a large group of neuropsychiatric illnesses that occur during early brain development, resulting in a broad spectrum of syndromes affecting cognition, sociability, and sensory and motor functions. Despite progress in [...] Read more.

Neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASD) and intellectual disability (ID), are a large group of neuropsychiatric illnesses that occur during early brain development, resulting in a broad spectrum of syndromes affecting cognition, sociability, and sensory and motor functions. Despite progress in the discovery of various genetic risk factors thanks to the development of novel genomics technologies, the precise pathological mechanisms underlying the onset of NDDs remain elusive owing to the profound genetic and phenotypic heterogeneity of these conditions. Autism susceptibility candidate 2 (AUTS2) has emerged as a crucial gene associated with a wide range of neuropsychological disorders, such as ASD, ID, schizophrenia, and epilepsy. AUTS2 has been shown to be involved in multiple neurodevelopmental processes; in cell nuclei, it acts as a key transcriptional regulator in neurodevelopment, whereas in the cytoplasm, it participates in cerebral corticogenesis, including neuronal migration and neuritogenesis, through the control of cytoskeletal rearrangements. Postnatally, AUTS2 regulates the number of excitatory synapses to maintain the balance between excitation and inhibition in neural circuits. In this review, we summarize the knowledge regarding AUTS2, including its molecular and cellular functions in neurodevelopment, its genetics, and its role in behaviors. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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23 pages, 1848 KiB

Open AccessReview

Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

by Marcello Scala, Masashi Nishikawa, Koh-ichi Nagata and Pasquale Striano

Cells 2021, 10(12), 3395; https://doi.org/10.3390/cells10123395 - 02 Dec 2021

Cited by 17 | Viewed by 2916

Abstract

Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1–3. The proper function of Rac1 and [...] Read more.

Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1–3. The proper function of Rac1 and Rac3, and their correct interaction with guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) are crucial for neural development. Pathogenic variants affecting these delicate biological processes are implicated in different medical conditions in humans, primarily neurodevelopmental disorders (NDDs). In addition to a direct deleterious effect produced by genetic variants in the RAC genes, a dysregulated GTPase activity resulting from an abnormal function of GEFs and GAPs has been involved in the pathogenesis of distinctive emerging conditions. In this study, we reviewed the current pertinent literature on Rac-related disorders with a primary neurological involvement, providing an overview of the current knowledge on the pathophysiological mechanisms involved in the neuro-RACopathies. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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14 pages, 4719 KiB

Open AccessFeature PaperReview

Interneuron Dysfunction and Inhibitory Deficits in Autism and Fragile X Syndrome

by Toshihiro Nomura

Cells 2021, 10(10), 2610; https://doi.org/10.3390/cells10102610 - 01 Oct 2021

Cited by 20 | Viewed by 3651

Abstract

The alteration of excitatory–inhibitory (E–I) balance has been implicated in various neurological and psychiatric diseases, including autism spectrum disorder (ASD). Fragile X syndrome (FXS) is a single-gene disorder that is the most common known cause of ASD. Understanding the molecular and physiological features [...] Read more.

The alteration of excitatory–inhibitory (E–I) balance has been implicated in various neurological and psychiatric diseases, including autism spectrum disorder (ASD). Fragile X syndrome (FXS) is a single-gene disorder that is the most common known cause of ASD. Understanding the molecular and physiological features of FXS is thought to enhance our knowledge of the pathophysiology of ASD. Accumulated evidence implicates deficits in the inhibitory circuits in FXS that tips E–I balance toward excitation. Deficits in interneurons, the main source of an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), have been reported in FXS, including a reduced number of cells, reduction in intrinsic cellular excitability, or weaker synaptic connectivity. Manipulating the interneuron activity ameliorated the symptoms in the FXS mouse model, which makes it reasonable to conceptualize FXS as an interneuronopathy. While it is still poorly understood how the developmental profiles of the inhibitory circuit go awry in FXS, recent works have uncovered several developmental alterations in the functional properties of interneurons. Correcting disrupted E–I balance by potentiating the inhibitory circuit by targeting interneurons may have a therapeutic potential in FXS. I will review the recent evidence about the inhibitory alterations and interneuron dysfunction in ASD and FXS and will discuss the future directions of this field. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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11 pages, 991 KiB

Open AccessReview

Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders

by Toshiyuki Yamamoto

Cells 2021, 10(9), 2317; https://doi.org/10.3390/cells10092317 - 04 Sep 2021

Cited by 6 | Viewed by 2254

Abstract

Genomic studies are increasingly revealing that neurodevelopmental disorders are caused by underlying genomic alterations. Chromosomal microarray testing has been used to reliably detect minute changes in genomic copy numbers. The genes located in the aberrated regions identified in patients with neurodevelopmental disorders may [...] Read more.

Genomic studies are increasingly revealing that neurodevelopmental disorders are caused by underlying genomic alterations. Chromosomal microarray testing has been used to reliably detect minute changes in genomic copy numbers. The genes located in the aberrated regions identified in patients with neurodevelopmental disorders may be associated with the phenotypic features. In such cases, haploinsufficiency is considered to be the mechanism, when the deletion of a gene is related to neurodevelopmental delay. The loss-of-function mutation in such genes may be evaluated using next-generation sequencing. On the other hand, the patients with increased copy numbers of the genes may exhibit different clinical symptoms compared to those with loss-of-function mutation in the genes. In such cases, the additional copies of the genes are considered to have a dominant negative effect, inducing cell stress. In other cases, not the copy number changes, but mutations of the genes are responsible for causing the clinical symptoms. This can be explained by the dominant negative effects of the gene mutations. Currently, the diagnostic yield of genomic alterations using comprehensive analysis is less than 50%, indicating the existence of more subtle alterations or genomic changes in the untranslated regions. Copy-neutral inversions and insertions may be related. Hence, better analytical algorithms specialized for the detection of such alterations are required for higher diagnostic yields. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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15 pages, 508 KiB

Open AccessReview

Pathophysiological Roles of Abnormal Axon Initial Segments in Neurodevelopmental Disorders

by Masashi Fujitani, Yoshinori Otani and Hisao Miyajima

Cells 2021, 10(8), 2110; https://doi.org/10.3390/cells10082110 - 17 Aug 2021

Cited by 7 | Viewed by 4034

Abstract

The 20–60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural properties regulated by the crucial protein, ankyrin-G. The AIS contains a high density of Na⁺ channels relative [...] Read more.

The 20–60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural properties regulated by the crucial protein, ankyrin-G. The AIS contains a high density of Na⁺ channels relative to the cell body, which allows low thresholds for the initiation of action potential (AP). Molecular and physiological studies have shown that the AIS is also a key domain for the control of neuronal excitability by homeostatic mechanisms. The AIS has high plasticity in normal developmental processes and pathological activities, such as injury, neurodegeneration, and neurodevelopmental disorders (NDDs). In the first half of this review, we provide an overview of the molecular, structural, and ion-channel characteristics of AIS, AIS regulation through axo-axonic synapses, and axo−glial interactions. In the second half, to understand the relationship between NDDs and AIS, we discuss the activity-dependent plasticity of AIS, the human mutation of AIS regulatory genes, and the pathophysiological role of an abnormal AIS in NDD model animals and patients. We propose that the AIS may provide a potentially valuable structural biomarker in response to abnormal network activity in vivo as well as a new treatment concept at the neural circuit level. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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