scholarly journals The structure of Neurexin 1α (n1α) and its role as synaptic organizer

Bionatura ◽  
2019 ◽  
Vol 4 (2) ◽  
pp. 883-886
Author(s):  
Marjorie Zambonino ◽  
Pamela Pereira
Keyword(s):  
Protein Complexes ◽  
Autism Spectrum ◽  
Knock Out ◽  
Adhesion Protein ◽  
Neuropsychiatric Diseases ◽  
Transmission Of Information ◽  
Complex Protein ◽  
Spectrum Disorders ◽  
Knock Out Mice ◽  
The Brain

α - and b-neurexins (NRXNs) are transmembrane adhesion protein complexes localized in presynaptic membranes into neurons and interact with the postsynaptic neuroligins (NLGNs). Our findings indicate that the neurexin 1α (n1α) is a synaptic organizer that directs postsynaptic development in neurons, evidenced in GABAergic neurons and trials with Knock-out Mice. Also, the interactions between hypervariable surfaces of n1α and ligands (neurexophilin, a-dystroglycan, and GABAA) promotes a proper protein-binding recognition, and consequently, a better synaptic adhesion. There is a direct relationship between mental disorders and the n1α assemblage because NRXN1 gene encodes for n1α proteins which are involved in the transmission of information into the brain. For this reason, damage in this complex-protein or some neurexin gene variations causes pathological abnormalities and neuropsychiatric diseases such as schizophrenia, autism spectrum disorders, and intellectual disabilities.

Dysregulation of DNA methylation during development as a potential mechanisms contributing to obsessive compulsive disorders and autism

2019 ◽  
Author(s):  
German I. Todorov ◽  
Karthikeyan Mayilvahanan ◽  
David Ashurov ◽  
Catarina Cunha
Keyword(s):  
Mouse Model ◽  
Autism Spectrum ◽  
Obsessive Compulsive ◽  
Cancer Treatments ◽  
Knock Out ◽  
Treatment Priority ◽  
Underlying Mechanisms ◽  
Knock Out Mice ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder, that is raising at a concerning rate. However, underlying mechanisms are still to be discovered. Obsessions and compulsions are the most debilitating aspect of these disorders (OCD), and they are the treatment priority for patients. SAPAP3 knock out mice present a reliable mouse model for repetitive compulsive behavior and are mechanistically closely related to the ASD mouse model Shank3 on a molecular level and AMPA receptor net effect. The phenotype of SAPAP3 knock out mice is obsessive grooming that leads to self-inflicted lesions by 4 months of age. Recent studies have accumulated evidence, that epigenetic mechanisms are important effectors in psychiatric conditions such as ASD and OCD. Methylation is the most studied mechanism, that recently lead to drug developments for more precise cancer treatments. We injected SAPAP3 mice with an epigenetic demethylation drug RG108 during pregnancy and delayed the onset of the phenotype in the offspring by 4 months. This result gives us clues about possible mechanism involved in OCD and ASD. Additionally, it shows that modulation of methylation mechanisms during development might be explored as a preventative treatment in the cases of high inherited risk of certain mental health conditions.

Differentiation of Healthy Individuals from Those with Autism Spectrum Disorders using Information Graph of Complementary Opposites

2020 ◽  
Keyword(s):  
Children With Autism ◽  
Autism Spectrum ◽  
Brain Signals ◽  
Three Stages ◽  
The Mean ◽  
Spectrum Disorders ◽  
Pediatric Psychiatry ◽  
The Brain ◽  
Optimal Feature ◽  
Information Graph

This study aimed to examine the brain signals of children with Autism Spectrum Disorder (ASD) and use a method according to the concept of complementary opposites to obtain the prominent features or a pattern of EEG signal that represents the biological characteristic of such children. In this study, 20 children with the mean±SD age of 8±5 years were divided into two groups of normal control (NC) and ASD. The diagnosis and approval of individuals in both groups were conducted by two experts in the field of pediatric psychiatry and neurology. The recording protocol was designed with the most accuracy; therefore, the brain signals were recorded with the least noise in the awake state of the individuals in both groups. Moreover, the recording was conducted in three stages from two channels (C3-C4) of EEG ( referred to as the central part of the brain) which were symmetrical in function. In this study, the Mandala method was adopted based on the concept of complementary opposites to investigate the features extracted from Mandala pattern topology and obtain new features and pseudo-patterns for the screening and early diagnosis of ASD. The optimal feature here was based on different stages of processing and statistical analysis of Pattern Detection Capability (PDC). The PDC is a biomarker derived from the Mandala pattern for differentiating the NC from ASD groups.

scholarly journals The Role of Iron in the Pathogenesis of Autism Spectrum Disorders in Children

2018 ◽  
Vol 17 (4) ◽  
pp. 281-286 ◽  
Author(s):  
Olga V. Kostina
Keyword(s):  
Autism Spectrum Disorders ◽  
Iron Metabolism ◽  
Biochemical Parameters ◽  
Children With Autism ◽  
Neuropsychiatric Disorders ◽  
Perinatal Period ◽  
Autism Spectrum ◽  
Spectrum Disorders ◽  
The Brain

The review presents an analysis of the mechanisms of iron effect on the brain development. The importance of iron deficiency in the perinatal period is considered as a risk factor for the development of neuropsychiatric disorders in children with autism spectrum disorders (ASDs). Possible causes of sideropenia are discussed; data on haematological and biochemical parameters characterizing iron metabolism in children with ASDs are presented. The demand for studying the role of iron metabolism imbalance in the development of neuropsychiatric disorders in order to clarify pathogenetic mechanisms of ASDs and to determine methods for their correction is emphasized.

The epigenetic regulation of synaptic genes contributes to the etiology of autism

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Annamaria Srancikova ◽  
Zuzana Bacova ◽  
Jan Bakos
Keyword(s):  
Epigenetic Regulation ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Prader Willi Syndrome ◽  
Epigenetic Mechanisms ◽  
Substantial Evidence ◽  
Autistic Symptoms ◽  
Spectrum Disorders ◽  
The Brain

Abstract Epigenetic mechanisms greatly affect the developing brain, as well as the maturation of synapses with pervasive, long-lasting consequences on behavior in adults. Substantial evidence exists that implicates dysregulation of epigenetic mechanisms in the etiology of neurodevelopmental disorders. Therefore, this review explains the role of enzymes involved in DNA methylation and demethylation in neurodevelopment by emphasizing changes of synaptic genes and proteins. Epigenetic causes of sex-dependent differences in the brain are analyzed in conjunction with the pathophysiology of autism spectrum disorders. Special attention is devoted to the epigenetic regulation of the melanoma-associated antigen-like gene 2 (MAGEL2) found in Prader-Willi syndrome, which is known to be accompanied by autistic symptoms.

scholarly journals Altered Intestinal Morphology and Microbiota Composition in the Autism Spectrum Disorders Associated SHANK3 Mouse Model

2019 ◽  
Vol 20 (9) ◽  
pp. 2134 ◽  
Author(s):  
Ann Katrin Sauer ◽  
Juergen Bockmann ◽  
Konrad Steinestel ◽  
Tobias M. Boeckers ◽  
Andreas M. Grabrucker
Keyword(s):  
Autism Spectrum Disorders ◽  
Inflammatory Responses ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Intestinal Morphology ◽  
Microbiota Composition ◽  
Knock Out ◽  
E Coli ◽  
The Central Nervous System ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin repeat domains (SHANK) gene-family were identified in patients with ASD, and Shank knock-out mouse models display autism-like phenotypes. SHANK3 proteins are not only expressed in the central nervous system (CNS). Here, we show expression in gastrointestinal (GI) epithelium and report a significantly different GI morphology in Shank3 knock-out (KO) mice. Further, we detected a significantly altered microbiota composition measured in feces of Shank3 KO mice that may contribute to inflammatory responses affecting brain development. In line with this, we found higher E. coli lipopolysaccharide levels in liver samples of Shank3 KO mice, and detected an increase in Interleukin-6 and activated astrocytes in Shank3 KO mice. We conclude that apart from its well-known role in the CNS, SHANK3 plays a specific role in the GI tract that may contribute to the ASD phenotype by extracerebral mechanisms.

scholarly journals The influence of calcium signaling on the development of autism spectrum disorders

2020 ◽  
pp. 106-117
Author(s):  
Н.В. Соловьева ◽  
С.В. Чаусова ◽  
И.В. Кичук ◽  
Е.В. Макарова
Keyword(s):  
Autism Spectrum Disorders ◽  
Calcium Signaling ◽  
Signaling Pathway ◽  
Neuronal Damage ◽  
Long Term Potentiation ◽  
Autism Spectrum ◽  
Future Research ◽  
Calcium Signaling Pathway ◽  
Neuropsychiatric Diseases ◽  
Spectrum Disorders

Расстройства аутистического спектра (РАС) являются сложной группой нейропсихиатрических заболеваний с точки зрения этиопатогенеза. В основе нейрональных нарушений, приводящих к аутистической симптоматике, лежат дисфункции сигнальных путей. Согласно последним исследованиям одним из наиболее значимых сигнальных путей в развитии данной группы заболеваний является кальциевый сигнальный путь. Кальциевая сигнализация тесно связана с такими сигнальными путями, как MAPK-, Wnt-, PI3K/AKT/mTOR-, нарушение в работе которых приводит к нарушениям серотонинергической, дофаминергической, опиоидной, холинергической, глутаматергической, ГАМКергической передачи и влечет за собой эксайтотоксичность за счёт гиперактивации NMDA- и AMPA-рецепторов, повреждение и гибель нейронов. Все эти процессы в нейрональных клетках напрямую связаны с формированием долговременного потенцирования и депрессии, а нарушения в этих клетках приводят к дисфункции базисных психических процессов. С клинической точки зрения кальциевый сигнальный путь может стать одной из основных мишеней для фармакологической коррекции симптоматических проявлений РАС. Очевидно, что дальнейшие исследования на животных моделях и электрофизиологические клинические исследования необходимы для понимания патогенетических особенностей развития РАС, а также какое именно место занимает сигнальный путь Ca 2+ в данных состояниях. Дальнейшие исследования необходимы, для прояснения потенциальной роли сигнализации Ca 2+в изменениях социального или стериотипического поведении пациентов, что является основной обенностью РАС. Autism spectrum disorders (ASDs) are a group of neuropsychiatric diseases with a complex etiopathogenesis. Neuronal disorders leading to autistic symptoms are determined by dysfunction of signaling pathways. Recent studies have demonstrated that the calcium signaling pathway is one of the major significant pathways for this group of disorders. Calcium signaling is closely linked to MAPK-, Wnt-, and PI3K/AKT/mTOR -pathways, which abnormalities lead to dysfunction of serotonergic, dopaminergic, opioidergic, cholinergic, glutamatergic, and GABAergic transmission and result in excitotoxicity due to hyperactivation of NMDA and AMPA receptors and neuronal damage and death. These processes in neuronal cells are associated with formation of long-term potentiation and depression, and disturbances in these cells lead to failure of basic mental processes. From a clinical point of view, the calcium signaling pathway can become one of major targets for the pharmacological treatment of symptomatic ASD. Obviously, further animal studies and electrophysiological human studies are required for understanding pathogenetic mechanisms of ASD and the contribution of Ca 2+ signaling. Future research will clarify a potential role of Ca 2+ signaling in social or stereotypic behavior, which constitutes a main feature of ADS.

scholarly journals Inhibiting proBDNF to mature BDNF conversion leads to autism-like phenotypes in vivo

2020 ◽  
Author(s):  
He You ◽  
Toshiyuki Mizui ◽  
Kazuyuki Kiyosue ◽  
Keizo Takao ◽  
Tsuyoshi Miyakawa ◽  
...  
Keyword(s):  
Autism Spectrum ◽  
Synaptic Function ◽  
Early Age ◽  
Mouse Line ◽  
Brain Volumes ◽  
Blood Marker ◽  
Spectrum Disorders ◽  
Neurodevelopment Disorders ◽  
The Brain

AbstractAutism spectrum disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is oppositely regulated by brain-derived neurotrophic factor (BDNF): the precursor proBDNF inhibits while mature BDNF (mBDNF) potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is inhibited. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed decreased brain volumes, reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity. They also exhibited ASD-like phenotypes, including stereotypical behaviors, deficits in social interaction, hyperactivity, and elevated stress response. Interestingly, the plasma level of proBDNF, but not mBDNF, was significantly elevated in ASD patients. These results suggest that proBDNF level, but not Bdnf gene, is associated with autism-spectrum behaviors, and identify a potential blood marker and therapeutic target for ASD.

scholarly journals Reduction of cortical parvalbumin expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition

Development ◽  
2021 ◽  
Author(s):  
Till Scheuer ◽  
Elena auf dem Brinke ◽  
Sabine Grosser ◽  
Susanne A. Wolf ◽  
Daniele Mattei ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Psychiatric Symptoms ◽  
Autism Spectrum ◽  
Morphological Properties ◽  
Behavioral Deficits ◽  
Hyperactivity Disorder ◽  
Spectrum Disorders ◽  
The Brain ◽  
Psychiatric Problems ◽  
Behavior And Cognition

The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and others. These disorders are influenced not only by genetic but also by environmental factors, such as preterm birth, although the mechanisms underlying are not known. In a translational hyperoxia model, exposing mice pups at age P5 to 80% oxygen for 48 hours to mimic a steep rise of oxygen exposure caused by preterm birth from in utero into room air, we documented a persistent reduction of cortical mature parvalbumin expressing interneurons until adulthood. Developmental delay of cortical myelin was observed together with decreased expression of oligodendroglial glial cell-derived neurotrophic factor (GDNF), a factor being involved in interneuronal development. Electrophysiological and morphological properties of remaining interneurons were unaffected. Behavioral deficits were observed for social interaction, learning, and attention. These results elucidate that neonatal oxidative stress can lead to decreased interneuron density and to psychiatric symptoms. The obtained cortical myelin deficit and decreased oligodendroglial GDNF expression indicate an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.

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