International Journal of Molecular Sciences

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28 pages, 6173 KiB

Open AccessArticle

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy

by Elena G. Varlamova, Ekaterina V. Borisova, Yuliya A. Evstratova, Andrew G. Newman, Vera P. Kuldaeva, Maria S. Gavrish, Elena V. Kondakova, Victor S. Tarabykin, Alexey A. Babaev and Egor A. Turovsky

Int. J. Mol. Sci. 2023, 24(23), 17104; https://doi.org/10.3390/ijms242317104 - 4 Dec 2023

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Abstract

Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. [...] Read more.

Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. The genesis of epilepsy has been extensively investigated in terms of its occurrence after injury and as a concomitant disease with various brain diseases, such as tumors, ischemic events, etc. However, in the last decades, there are multiple reports that both genetic and epigenetic factors play an important role in epileptogenesis. Therefore, there is a need for further identification of genes and loci that can be associated with higher susceptibility to epileptic seizures. Use of mouse knockout models of epileptogenesis is very informative, but it has its limitations. One of them is due to the fact that complete deletion of a gene is not, in many cases, similar to human epilepsy-associated syndromes. Another approach to generating mouse models of epilepsy is N-Ethyl-N-nitrosourea (ENU)-directed mutagenesis. Recently, using this approach, we generated a novel mouse strain, soc (socrates, formerly s8-3), with epileptiform activity. Using molecular biology methods, calcium neuroimaging, and immunocytochemistry, we were able to characterize the strain. Neurons isolated from soc mutant brains retain the ability to differentiate in vitro and form a network. However, soc mutant neurons are characterized by increased spontaneous excitation activity. They also demonstrate a high degree of Ca²⁺ activity compared to WT neurons. Additionally, they show increased expression of NMDA receptors, decreased expression of the Ca²⁺-conducting GluA2 subunit of AMPA receptors, suppressed expression of phosphoinositol 3-kinase, and BK channels of the cytoplasmic membrane involved in protection against epileptogenesis. During embryonic and postnatal development, the expression of several genes encoding ion channels is downregulated in vivo, as well. Our data indicate that soc mutation causes a disruption of the excitation–inhibition balance in the brain, and it can serve as a mouse model of epilepsy. Full article

(This article belongs to the Special Issue Research of Neuronal Cell in Nervous System Development and Disease)

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20 pages, 10211 KiB

Open AccessArticle

β-Catenin and SOX2 Interaction Regulate Visual Experience-Dependent Cell Homeostasis in the Developing Xenopus Thalamus

by Juanmei Gao, Yufang Lu, Yuhao Luo, Xinyi Duan, Peiyao Chen, Xinyu Zhang, Xiaohua Wu, Mengsheng Qiu and Wanhua Shen

Int. J. Mol. Sci. 2023, 24(17), 13593; https://doi.org/10.3390/ijms241713593 - 2 Sep 2023

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Abstract

In the vertebrate brain, sensory experience plays a crucial role in shaping thalamocortical connections for visual processing. However, it is still not clear how visual experience influences tissue homeostasis and neurogenesis in the developing thalamus. Here, we reported that the majority of SOX2-positive [...] Read more.

In the vertebrate brain, sensory experience plays a crucial role in shaping thalamocortical connections for visual processing. However, it is still not clear how visual experience influences tissue homeostasis and neurogenesis in the developing thalamus. Here, we reported that the majority of SOX2-positive cells in the thalamus are differentiated neurons that receive visual inputs as early as stage 47 Xenopus. Visual deprivation (VD) for 2 days shifts the neurogenic balance toward proliferation at the expense of differentiation, which is accompanied by a reduction in nuclear-accumulated β-catenin in SOX2-positive neurons. The knockdown of β-catenin decreases the expression of SOX2 and increases the number of progenitor cells. Coimmunoprecipitation studies reveal the evolutionary conservation of strong interactions between β-catenin and SOX2. These findings indicate that β-catenin interacts with SOX2 to maintain homeostatic neurogenesis during thalamus development. Full article

(This article belongs to the Special Issue Research of Neuronal Cell in Nervous System Development and Disease)

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36 pages, 5063 KiB

Open AccessArticle

A Novel Rat Model of ADHD-like Hyperactivity/Impulsivity after Delayed Reward Has Selective Loss of Dopaminergic Neurons in the Right Ventral Tegmental Area

by Sarah E. Kohe, Emma K. Gowing, Steve Seo and Dorothy E. Oorschot

Int. J. Mol. Sci. 2023, 24(14), 11252; https://doi.org/10.3390/ijms241411252 - 8 Jul 2023

Cited by 1 | Viewed by 1464

Abstract

In attention deficit hyperactivity disorder (ADHD), hyperactivity and impulsivity occur in response to delayed reward. Herein we report a novel animal model in which male Sprague-Dawley rats exposed to repeated hypoxic brain injury during the equivalent of extreme prematurity were ADHD-like hyperactive/impulsive in [...] Read more.

In attention deficit hyperactivity disorder (ADHD), hyperactivity and impulsivity occur in response to delayed reward. Herein we report a novel animal model in which male Sprague-Dawley rats exposed to repeated hypoxic brain injury during the equivalent of extreme prematurity were ADHD-like hyperactive/impulsive in response to delayed reward and attentive at 3 months of age. Thus, a unique animal model of one of the presentations/subtypes of ADHD was discovered. An additional finding is that the repeated hypoxia rats were not hyperactive in the widely used open field test, which is not ADHD specific. Hence, it is recommended that ADHD-like hyperactivity and ADHD-like impulsivity, specifically in response to delayed reward, be a primary component in the design of future experiments that characterize potential animal models of ADHD, replacing open field testing of hyperactivity. Unknown is whether death and/or activity of midbrain dopaminergic neurons contributed to the ADHD-like hyperactivity/impulsivity detected after delayed reward. Hence, we stereologically measured the absolute number of dopaminergic neurons in four midbrain subregions and the average somal/nuclear volume of those neurons. Repeated hypoxia rats had a significant specific loss of dopaminergic neurons in the right ventral tegmental area (VTA) at 2 weeks of age and 18 months of age, providing new evidence of a site of pathology. No dopaminergic neuronal loss occurred in three other midbrain regions. Fewer VTA dopaminergic neurons correlated with increased ADHD-like hyperactivity and impulsivity. Novel early intervention therapies to rescue VTA dopaminergic neurons and potentially prevent ADHD-like hyperactivity/impulsivity can now be investigated. Full article

(This article belongs to the Special Issue Research of Neuronal Cell in Nervous System Development and Disease)

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13 pages, 10160 KiB

Open AccessArticle

The Biological Behaviors of Neural Stem Cell Affected by Microenvironment from Host Organotypic Brain Slices under Different Conditions

by Qian Jiao, Li Wang, Zhichao Zhang, Xinlin Chen, Haixia Lu and Yong Liu

Int. J. Mol. Sci. 2023, 24(4), 4182; https://doi.org/10.3390/ijms24044182 - 20 Feb 2023

Cited by 1 | Viewed by 1394

Abstract

Therapeutic strategies based on neural stem cells (NSCs) transplantation bring new hope for neural degenerative disorders, while the biological behaviors of NSCs after being grafted that were affected by the host tissue are still largely unknown. In this study, we engrafted NSCs that [...] Read more.

Therapeutic strategies based on neural stem cells (NSCs) transplantation bring new hope for neural degenerative disorders, while the biological behaviors of NSCs after being grafted that were affected by the host tissue are still largely unknown. In this study, we engrafted NSCs that were isolated from a rat embryonic cerebral cortex onto organotypic brain slices to examine the interaction between grafts and the host tissue both in normal and pathological conditions, including oxygen–glucose deprivation (OGD) and traumatic injury. Our data showed that the survival and differentiation of NSCs were strongly influenced by the microenvironment of the host tissue. Enhanced neuronal differentiation was observed in normal conditions, while significantly more glial differentiation was observed in injured brain slices. The process growth of grafted NSCs was guided by the cytoarchitecture of host brain slices and showed the distinct difference between the cerebral cortex, corpus callosum and striatum. These findings provided a powerful resource for unraveling how the host environment determines the fate of grafted NSCs, and raise the prospect of NSCs transplantation therapy for neurological diseases. Full article

(This article belongs to the Special Issue Research of Neuronal Cell in Nervous System Development and Disease)

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15 pages, 2816 KiB

Open AccessArticle

Cell Fate of Retinal Progenitor Cells: In Ovo UbC-StarTrack Analysis

by Cindy L. Olmos-Carreño, María Figueres-Oñate, Gabriel E. Scicolone and Laura López-Mascaraque

Int. J. Mol. Sci. 2022, 23(20), 12388; https://doi.org/10.3390/ijms232012388 - 16 Oct 2022

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Abstract

Clonal cell analysis outlines the ontogenic potential of single progenitor cells, allowing the elucidation of the neural heterogeneity among different cell types and their lineages. In this work, we analyze the potency of retinal stem/progenitor cells through development using the chick embryo as [...] Read more.

Clonal cell analysis outlines the ontogenic potential of single progenitor cells, allowing the elucidation of the neural heterogeneity among different cell types and their lineages. In this work, we analyze the potency of retinal stem/progenitor cells through development using the chick embryo as a model. We implemented in ovo the clonal genetic tracing strategy UbC-StarTrack for tracking retinal cell lineages derived from individual progenitors of the ciliary margin at E3.5 (HH21-22). The clonal assignment of the derived-cell progeny was performed in the neural retina at E11.5-12 (HH38) through the identification of sibling cells as cells expressing the same combination of fluorophores. Moreover, cell types were assessed based on their cellular morphology and laminar location. Ciliary margin derived-cell progenies are organized in columnar associations distributed along the peripheral retina with a limited tangential dispersion. The analysis revealed that, at the early stages of development, this region harbors multipotent and committed progenitor cells. Full article

(This article belongs to the Special Issue Research of Neuronal Cell in Nervous System Development and Disease)

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21 pages, 7034 KiB

Open AccessArticle

Dp71 Point Mutations Induce Protein Aggregation, Loss of Nuclear Lamina Integrity and Impaired Braf35 and Ibraf Function in Neuronal Cells

by Claudia Ivette Rugerio-Martínez, Daniel Ramos, Abel Segura-Olvera, Nadia Mireya Murillo-Melo, Yessica Sarai Tapia-Guerrero, Raúl Argüello-García, Norberto Leyva-García, Oscar Hernández-Hernández, Bulmaro Cisneros and Rocío Suárez-Sánchez

Int. J. Mol. Sci. 2022, 23(19), 11876; https://doi.org/10.3390/ijms231911876 - 6 Oct 2022

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Abstract

Dystrophin Dp71 is the most abundant product of the Duchenne muscular dystrophy gene in the nervous system, and mutations impairing its function have been associated with the neurodevelopmental symptoms present in a third of DMD patients. Dp71 is required for the clustering of [...] Read more.

Dystrophin Dp71 is the most abundant product of the Duchenne muscular dystrophy gene in the nervous system, and mutations impairing its function have been associated with the neurodevelopmental symptoms present in a third of DMD patients. Dp71 is required for the clustering of neurotransmitter receptors and the neuronal differentiation of cultured cells; nonetheless, its precise role in neuronal cells remains to be poorly understood. In this study, we analyzed the effect of two pathogenic DMD gene point mutations on the Dp71 function in neurons. We engineered C272Y and E299del mutations to express GFP-tagged Dp71 protein variants in N1E-115 and SH-SY5Y neuronal cells. Unexpectedly, the ectopic expression of Dp71 mutants resulted in protein aggregation, which may be mechanistically caused by the effect of the mutations on Dp71 structure, as predicted by protein modeling and molecular dynamics simulations. Interestingly, Dp71 mutant variants acquired a dominant negative function that, in turn, dramatically impaired the distribution of different Dp71 protein partners, including β-dystroglycan, nuclear lamins A/C and B1, the high-mobility group (HMG)-containing protein (BRAF35) and the BRAF35-family-member inhibitor of BRAF35 (iBRAF). Further analysis of Dp71 mutants provided evidence showing a role for Dp71 in modulating both heterochromatin marker H3K9me2 organization and the neuronal genes’ expression, via its interaction with iBRAF and BRAF5. Full article

(This article belongs to the Special Issue Research of Neuronal Cell in Nervous System Development and Disease)

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Review

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15 pages, 1538 KiB

Open AccessReview

Fluorescent Molecules That Help Reveal Previously Unidentified Neural Connections in Adult, Neonatal and Peripubertal Mammals

by Enikő Vasziné Szabó, Katalin Köves and Ágnes Csáki

Int. J. Mol. Sci. 2023, 24(19), 14478; https://doi.org/10.3390/ijms241914478 - 23 Sep 2023

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Abstract

One hundred and twenty-five years ago there was a lively discussion between Hungarian and Spanish neuroscientists on the nature of neural connections. The question was whether the neurofibrils run from one neuron to the next and connect neurons as a continuous network or [...] Read more.

One hundred and twenty-five years ago there was a lively discussion between Hungarian and Spanish neuroscientists on the nature of neural connections. The question was whether the neurofibrils run from one neuron to the next and connect neurons as a continuous network or the fibrils form an internal skeleton in the neurons and do not leave the cell; however, there is close contact between the neurons. About 50 years later, the invention of the electron microscope solved the problem. Close contacts between individual neurons were identified and named as synapses. In the following years, the need arose to explore distant connections between neuronal structures. Tracing techniques entered neuroscience. There are three major groups of tracers: (A) non-transsynaptic tracers used to find direct connections between two neuronal structures; (B) tracers passing gap junctions; (C) transsynaptic tracers passing synapses that are suitable to explore multineuronal circuits. According to the direction of the transport mechanism, the tracer may be ante- or retrograde. In this review, we focus on the ever-increasing number of fluorescent tracers that we have also used in our studies. The advantage of the use of these molecules is that the fluorescence of the tracer can be seen in histological sections without any other processes. Genes encoding fluorescent molecules can be inserted in various neuropeptide or neurotransmitter expressing transcriptomes. This makes it possible to study the anatomy, development or functional relations of these neuronal networks in transgenic animals. Full article

(This article belongs to the Special Issue Research of Neuronal Cell in Nervous System Development and Disease)

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20 pages, 970 KiB

Open AccessReview

The Role of MEF2 Transcription Factor Family in Neuronal Survival and Degeneration

by Malwina Lisek, Oskar Przybyszewski, Ludmila Zylinska, Feng Guo and Tomasz Boczek

Int. J. Mol. Sci. 2023, 24(4), 3120; https://doi.org/10.3390/ijms24043120 - 4 Feb 2023

Cited by 2 | Viewed by 3424

Abstract

The family of myocyte enhancer factor 2 (MEF2) transcription factors comprises four highly conserved members that play an important role in the nervous system. They appear in precisely defined time frames in the developing brain to turn on and turn off genes affecting [...] Read more.

The family of myocyte enhancer factor 2 (MEF2) transcription factors comprises four highly conserved members that play an important role in the nervous system. They appear in precisely defined time frames in the developing brain to turn on and turn off genes affecting growth, pruning and survival of neurons. MEF2s are known to dictate neuronal development, synaptic plasticity and restrict the number of synapses in the hippocampus, thus affecting learning and memory formation. In primary neurons, negative regulation of MEF2 activity by external stimuli or stress conditions is known to induce apoptosis, albeit the pro or antiapoptotic action of MEF2 depends on the neuronal maturation stage. By contrast, enhancement of MEF2 transcriptional activity protects neurons from apoptotic death both in vitro and in preclinical models of neurodegenerative diseases. A growing body of evidence places this transcription factor in the center of many neuropathologies associated with age-dependent neuronal dysfunctions or gradual but irreversible neuron loss. In this work, we discuss how the altered function of MEF2s during development and in adulthood affecting neuronal survival may be linked to neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Research of Neuronal Cell in Nervous System Development and Disease)

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