scholarly journals Probing the VIPR2 Microduplication Linkage to Schizophrenia in Animal and Cellular Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Yukio Ago ◽  
Satoshi Asano ◽  
Hitoshi Hashimoto ◽  
James A. Waschek
Keyword(s):  
Synaptic Plasticity ◽  
Brain Development ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Autism Spectrum ◽  
Cellular Models ◽  
Pituitary Adenylate Cyclase ◽  
Innervation Patterns ◽  
The Brain

Pituitary adenylate cyclase-activating polypeptide (PACAP, gene name ADCYAP1) is a multifunctional neuropeptide involved in brain development and synaptic plasticity. With respect to PACAP function, most attention has been given to that mediated by its specific receptor PAC1 (ADCYAP1R1). However, PACAP also binds tightly to the high affinity receptors for vasoactive intestinal peptide (VIP, VIP), called VPAC1 and VPAC2 (VIPR1 and VIPR2, respectively). Depending on innervation patterns, PACAP can thus interact physiologically with any of these receptors. VPAC2 receptors, the focus of this review, are known to have a pivotal role in regulating circadian rhythms and to affect multiple other processes in the brain, including those involved in fear cognition. Accumulating evidence in human genetics indicates that microduplications at 7q36.3, containing VIPR2 gene, are linked to schizophrenia and possibly autism spectrum disorder. Although detailed molecular mechanisms have not been fully elucidated, recent studies in animal models suggest that overactivation of the VPAC2 receptor disrupts cortical circuit maturation. The VIPR2 linkage can thus be potentially explained by inappropriate control of receptor signaling at a time when neural circuits involved in cognition and social behavior are being established. Alternatively, or in addition, VPAC2 receptor overactivity may disrupt ongoing synaptic plasticity during processes of learning and memory. Finally, in vitro data indicate that PACAP and VIP have differential activities on the maturation of neurons via their distinct signaling pathways. Thus perturbations in the balance of VPAC2, VPAC1, and PAC1 receptors and their ligands may have important consequences in brain development and plasticity.

“Neurodevelopment in a dish” Elucidates the Mechanisms of Autism Spectrum Disorder

2017 ◽  
Vol 41 (S1) ◽  
pp. s795-s795
Author(s):  
M. Ilieva ◽  
M. Kamand ◽  
K. Kolev ◽  
S.L. Forsberg ◽  
Å.F. Svenningsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Environmental Factors ◽  
Brain Development ◽  
Behavioral Flexibility ◽  
Autism Spectrum ◽  
Patient Specific ◽  
Cellular Models ◽  
The Brain

IntroductionAutism spectrum disorders (ASD) is a group of neurodevelopmental disorders characterized by deficits in social cognition, communication, and behavioral flexibility. Most of the cases appear to be caused by the combination of autism risk genes and environmental factors affecting early embryonal brain development. The current animal and 2D cellular models are not able to recapitulate the complex integrity of the developing brain. Therefore a model of the brain that can cast a light on the pathological processes during brain development is of a high need.Aim and objectivesThe aim of our research is to develop a three-dimensional brain organotypic system (brain organoids) for culturing patient's derived induced pluripotent stem cells (iPSC).MethodologyWe propose a multidisciplinary approach, involving the generation of patient specific iPSC from somatic cells (fibroblasts) and 3D culturing techniques to build a complex “humanized” in vitro platform for ASD research. Further we will investigate differences in gene expression of potential disease related markers and cellular phenotype between autistic patients and controls.ResultsBrain organoids have the ability to recreate the right complexity of the brain. On the cellular and gene expression level, organoids demonstrate a high similarity to the neurodevelopment in vivo and can therefore recapitulate early stages of the neurogenesis.ConclusionTo date organoids are the most relevant cellular in vitro platform for the understanding the mechanisms behind ADS pathology. Organoids are a good modeling system for elucidating the role of epigenetic and environmental factors for development of ASD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Generation of Vascularized Brain Organoids to Study Neurovascular Interactions

2022 ◽  
Author(s):  
Zhen-Ge Luo ◽  
Xin-Yao Sun ◽  
Xiang-Chun Ju ◽  
Yang Li ◽  
Peng-Ming Zeng ◽  
...  
Keyword(s):  
Brain Development ◽  
Neural Development ◽  
Immune Cells ◽  
Aging Process ◽  
Neural Progenitors ◽  
Brain Disorders ◽  
Specific Population ◽  
Neurovascular Interactions ◽  
The Brain

The recently developed brain organoids have been used to recapitulate the processes of brain development and related diseases. However, the lack of vasculatures, which regulate neurogenesis, brain disorders, and aging process, limits the utility of brain organoids. In this study, we induced vessel and brain organoids respectively, and then fused two types of organoids together to obtain vascularized brain organoids. The fused brain organoids were engrafted with robust vascular network-like structures, and exhibited increased number of neural progenitors, in line with the possibility that vessels regulate neural development. Fusion organoids also contained functional blood-brain-barrier (BBB)-like structures, as well as microglial cells, a specific population of immune cells in the brain. The incorporated microglia responded actively to immune stimuli to the fused brain organoids. Thus, the fusion organoids established in this study allow modeling interactions between the neuronal and non-neuronal components in vitro, in particular the vasculature and microglia niche.

Genipin Attenuates Tau Phosphorylation and Aβ Levels in Cellular Models of Alzheimer's Disease

2021 ◽  
Author(s):  
Meiting Li ◽  
Nan Cai ◽  
Liang Gu ◽  
Lijun Yao ◽  
Decheng Bi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Tau Phosphorylation ◽  
Brain Disorder ◽  
Cellular Models ◽  
Aβ Generation ◽  
Aβ Production

Abstract Alzheimer’s disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules are considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

MRI Characteristic of Cerebral White Matter Maturation Patterns in Normal Infants of Assisted Reproductive

2020 ◽  
Author(s):  
Xiaoming Wu ◽  
Junfeng Wang ◽  
Libo Zou ◽  
Xiaojian Cui ◽  
Youcheng Wang ◽  
...  
Keyword(s):  
Brain Development ◽  
Cerebral White Matter ◽  
Vitro Fertilization ◽  
Brain Scans ◽  
Number Of Children ◽  
Significant Difference ◽  
Mri Scans ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Abstract Background Assisted reproductive technology (ART) such as in-vitro fertilization (IVF) and embryo transfer (ET) has been essential in the treatment of infertility, and the number of children born after these procedures has now passed 5 million worldwide. Children born after medically assisted reproduction are at higher risk of adverse birth outcomes than are children conceived naturally. In this study, we leveraged MRI technology to investigate whether ART pregnancy methods: intracytoplasmic sperm injection (ICSI) and ET have any effect on the brain development of offspring by comparing with the NAT pregnancy method. Methods A total of 75 infants were recruited in the study from 3 conception groups: 25 children born after ICSI, 25 children born after IVF-ET and 25 children born after natural pregnancy. Magnetic resonance imaging (MRI) scans provide exceptionally detailed information on how the human brain changes throughout childhood, adolescence, and old age. The use of MRI in the evaluation of the developing brain is well established. Results The results of routine brain scans on T1WI and T2WI showed that there was no significant difference among the 5-7, 11-13, and 23-25 months of infants among ET, ICSI, and NAT groups. The MRI values fluctuate at different time points indicating that they may change with the development of the brain. However, they are on a similar level for different conception groups supporting our previous statistical analysis that MRI values of ICSI and ET groups are not significantly different from NAT. Conclusions The results showed that there was no significant difference in brain development patterns between different modes of conception, which proved that ART does not affect the development of brain myelin in fetuses and infants.

Estrogens and progestins: molecular effects on brain cells

2010 ◽  
Vol 4 (3) ◽  
Author(s):  
Paolo Mannella ◽  
Tommaso Simoncini ◽  
Andrea Riccardo Genazzani
Keyword(s):  
Sex Steroids ◽  
Molecular Mechanisms ◽  
Neural Cells ◽  
Protective Effects ◽  
Complete Knowledge ◽  
Molecular Effects ◽  
In Vivo Effects ◽  
The Brain

AbstractSex steroids are known to regulate brain function and their role is so important that several diseases are strictly correlated with the onset of menopause when estrogen-progesterone deficiency makes neural cells much more vulnerable to toxic stimuli. Although in the past years several scientists have focused their studies on in vitro and in vivo effects of sex steroids on the brain, we are still far from complete knowledge. Indeed, contrasting results from large clinical trials have made the entire issue much more complicated. Currently we know that protective effects exerted by sex steroids depend on several factors among which the dose, the health of the cells and the type of molecule being used. In this review, we present an overview of the direct and indirect effects of estrogen and progesterone on the brain with specific focus on the molecular mechanisms by which these molecules act on neural cells.

scholarly journals Molekulare Kontrolle der Stabilität und Plastizität von Synapsen

BIOspektrum ◽  
2021 ◽  
Vol 27 (6) ◽  
pp. 588-590
Author(s):  
Zeeshan Mushtaq ◽  
Jan Pielage
Keyword(s):  
Nervous System ◽  
Synaptic Plasticity ◽  
Neurodegenerative Diseases ◽  
Information Flow ◽  
Molecular Mechanisms ◽  
Synaptic Connectivity ◽  
Genetic Mutations ◽  
Neuronal Circuits ◽  
The Brain

AbstractThe precise regulation of synaptic connectivity is essential for the processing of information in the brain. Any aberrant loss of synaptic connectivity due to genetic mutations will disrupt information flow in the nervous system and may represent the underlying cause of psychiatric or neurodegenerative diseases. Therefore, identification of the molecular mechanisms controlling synaptic plasticity and maintenance is essential for our understanding of neuronal circuits in development and disease.

scholarly journals Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Minjin Jeong ◽  
Karen E. Ocwieja ◽  
Dongjun Han ◽  
P. Ashley Wackym ◽  
Yichen Zhang ◽  
...  
Keyword(s):  
Inner Ear ◽  
Hair Cells ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
In Vitro Models ◽  
Cellular Models ◽  
Induced Pluripotent ◽  
Human Inner Ear

Abstract Background COVID-19 is a pandemic respiratory and vascular disease caused by SARS-CoV-2 virus. There is a growing number of sensory deficits associated with COVID-19 and molecular mechanisms underlying these deficits are incompletely understood. Methods We report a series of ten COVID-19 patients with audiovestibular symptoms such as hearing loss, vestibular dysfunction and tinnitus. To investigate the causal relationship between SARS-CoV-2 and audiovestibular dysfunction, we examine human inner ear tissue, human inner ear in vitro cellular models, and mouse inner ear tissue. Results We demonstrate that adult human inner ear tissue co-expresses the angiotensin-converting enzyme 2 (ACE2) receptor for SARS-CoV-2 virus, and the transmembrane protease serine 2 (TMPRSS2) and FURIN cofactors required for virus entry. Furthermore, hair cells and Schwann cells in explanted human vestibular tissue can be infected by SARS-CoV-2, as demonstrated by confocal microscopy. We establish three human induced pluripotent stem cell (hiPSC)-derived in vitro models of the inner ear for infection: two-dimensional otic prosensory cells (OPCs) and Schwann cell precursors (SCPs), and three-dimensional inner ear organoids. Both OPCs and SCPs express ACE2, TMPRSS2, and FURIN, with lower ACE2 and FURIN expression in SCPs. OPCs are permissive to SARS-CoV-2 infection; lower infection rates exist in isogenic SCPs. The inner ear organoids show that hair cells express ACE2 and are targets for SARS-CoV-2. Conclusions Our results provide mechanistic explanations of audiovestibular dysfunction in COVID-19 patients and introduce hiPSC-derived systems for studying infectious human otologic disease.

scholarly journals The Neurobiology of Selenium: Looking Back and to the Future

2021 ◽  
Vol 15 ◽  
Author(s):  
Ulrich Schweizer ◽  
Simon Bohleber ◽  
Wenchao Zhao ◽  
Noelia Fradejas-Villar
Keyword(s):  
Cell Biology ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Epileptic Seizures ◽  
Cell Types ◽  
Mammalian Brain ◽  
The Individual ◽  
The Brain ◽  
Looking Back

Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.

scholarly journals Gene expression levels of DNA methyltransferase enzymes in Shank3-deficient mouse model of autism during early development

2021 ◽  
Vol 55 (4) ◽  
pp. 234-237
Author(s):  
Annamaria Srancikova ◽  
Alexandra Reichova ◽  
Zuzana Bacova ◽  
Jan Bakos
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Brain Development ◽  
Early Development ◽  
Molecular Mechanisms ◽  
Altered Expression ◽  
Expression Levels ◽  
The Brain ◽  
Deficient Mice ◽  
Gene Expression Levels

Abstract Objectives. The balance between DNA methylation and demethylation is crucial for the brain development. Therefore, alterations in the expression of enzymes controlling DNA methylation patterns may contribute to the etiology of neurodevelopmental disorders, including autism. SH3 and multiple ankyrin repeat domains 3 (Shank3)-deficient mice are commonly used as a well-characterized transgenic model to investigate the molecular mechanisms of autistic symptoms. DNA methyltransferases (DNMTs), which modulate several cellular processes in neurodevelopment, are implicated in the pathophysiology of autism. In this study, we aimed to describe the gene expression changes of major Dnmts in the brain of Shank3-deficient mice during early development. Methods and Results. The Dnmts gene expression was analyzed by qPCR in 5-day-old homo-zygous Shank3-deficient mice. We found significantly lower Dnmt1 and Dnmt3b gene expression levels in the frontal cortex. However, no such changes were observed in the hippocampus. However, significant increase was observed in the expression of Dnmt3a and Dnmt3b genes in the hypothalamus of Shank3-deficient mice. Conclusions. The present data indicate that abnormalities in the Shank3 gene are accompanied by an altered expression of DNA methylation enzymes in the early brain development stages, therefore, specific epigenetic control mechanisms in autism-relevant models should be more extensively investigated.

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