scholarly journals Astrocytes and Developmental Plasticity in Fragile X

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Connie Cheng ◽  
Mary Sourial ◽  
Laurie C. Doering
Keyword(s):  
Neurodevelopmental Disorders ◽  
Developmental Plasticity ◽  
Neural Circuits ◽  
Current Knowledge ◽  
Fragile X ◽  
Synaptic Function ◽  
Disease Phenotype ◽  
Postnatal Brain ◽  
Knowing That ◽  
And Function

A growing body of research indicates a pivotal role for astrocytes at the developing synapse. In particular, astrocytes are dynamically involved in governing synapse structure, function, and plasticity. In the postnatal brain, their appearance at synapses coincides with periods of developmental plasticity when neural circuits are refined and established. Alterations in the partnership between astrocytes and neurons have now emerged as important mechanisms that underlie neuropathology. With overall synaptic function standing as a prominent link to the expression of the disease phenotype in a number of neurodevelopmental disorders and knowing that astrocytes influence synapse development and function, this paper highlights the current knowledge of astrocyte biology with a focus on their involvement in fragile X syndrome.

scholarly journals Neurons interact with the microbiome: an evolutionary-informed perspective

Neuroforum ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Christoph Giez ◽  
Alexander Klimovich ◽  
Thomas C. G. Bosch
Keyword(s):  
Nervous System ◽  
Neural Circuits ◽  
Current Knowledge ◽  
System Development ◽  
Nervous System Development ◽  
Comprehensive Understanding ◽  
Strategic Model ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
And Function

Abstract Animals have evolved within the framework of microbes and are constantly exposed to diverse microbiota. Microbes colonize most, if not all, animal epithelia and influence the activity of many organs, including the nervous system. Therefore, any consideration on nervous system development and function in the absence of the recognition of microbes will be incomplete. Here, we review the current knowledge on the nervous systems of Hydra and its role in the host–microbiome communication. We show that recent advances in molecular and imaging methods are allowing a comprehensive understanding of the capacity of such a seemingly simple nervous system in the context of the metaorganism. We propose that the development, function and evolution of neural circuits must be considered in the context of host–microbe interactions and present Hydra as a strategic model system with great basic and translational relevance for neuroscience.

miRNAs in development and pathogenesis of the nervous system

2013 ◽  
Vol 41 (4) ◽  
pp. 815-820 ◽  
Author(s):  
Jakub S. Nowak ◽  
Gracjan Michlewski
Keyword(s):  
Nervous System ◽  
Present Article ◽  
Neurodevelopmental Disorders ◽  
Current Knowledge ◽  
And Function ◽  
Human Nervous System

The human nervous system expresses approximately 70% of all miRNAs (microRNAs). Changing levels of certain ubiquitous and brain-specific miRNAs shape the development and function of the nervous system. It is becoming clear that misexpression of some miRNAs can contribute towards neurodevelopmental disorders. In the present article, we review the current knowledge of the role of miRNAs in development and pathogenesis of the nervous system.

The behavioral neurogenetics of fragile X syndrome: Analyzing gene–brain–behavior relationships in child developmental psychopathologies

2003 ◽  
Vol 15 (4) ◽  
pp. 927-968 ◽  
Author(s):  
ALLAN L. REISS ◽  
CHRISTOPHER C. DANT
Keyword(s):  
Environmental Factors ◽  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Single Gene ◽  
Structure And Function ◽  
Research Approach ◽  
And Function ◽  
And Behavior ◽  
Brain Behavior

Analyzing gene–brain–behavior linkages in childhood neurodevelopmental disorders, a research approach called “behavioral neurogenetics,” has provided new insights into understanding how both genetic and environmental factors contribute to complex variations in typical and atypical human development. Research into etiologically more homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metrics of genetic risk so that we can more fully understand the complex pathophysiology of childhood onset neurodevelopmental disorders. In this paper, we review our laboratory's behavioral neurogenetics research by examining gene–brain–behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine genetic influences, trajectories of cognition and behavior, variation in brain structure and function, and biological and environmental factors that influence developmental and cognitive outcomes of children with fragile X. The converging approaches across these multilevel scientific domains indicate that fragile X, which arises from disruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations in neurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. In turn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in the child with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advanced our understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Our research and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are all different views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a more complete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding the complex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normal development by highlighting developmental events throughout the life span, thereby helping us to delineate the boundaries of pathology.

The influence of glucocorticoids on neuronal survival and synaptic function

2012 ◽  
Vol 3 (6) ◽  
pp. 495-504 ◽  
Author(s):  
Tadahiro Numakawa ◽  
Naoki Adachi ◽  
Misty Richards ◽  
Shuichi Chiba ◽  
Hiroshi Kunugi
Keyword(s):  
Current Knowledge ◽  
Neuronal Survival ◽  
Synaptic Function ◽  
Multiple Roles ◽  
Neuronal Populations ◽  
Animal Models Of Depression ◽  
The Central Nervous System ◽  
As Stress ◽  
And Function ◽  
The Impact

AbstractGlucocorticoids, recognized as stress-related steroid hormones secreted from adrenal glands, have multiple roles in brain function. The concentration of glucocorticoids is regulated by the hypothalamic-pituitary-adrenal axis, and chronically elevated levels of glucocorticoids are putatively involved in the pathophysiology of mental disorders, such as depression. As corticosteroids are also widely used as medical drugs (e.g., for chronic lung disease in infants), the developmental influence of glucocorticoids on neuronal survival and synaptic plasticity is a critical concern. Although many reports suggest a biological effect of glucocorticoids on neuronal populations of the central nervous system (CNS), some reports suggest a possibility that glial responses (including regulation of neurotrophic factor expression) to glucocorticoids are different from that of neurons. In the present review, we show an overview of the current knowledge concerning the impact of glucocorticoids on behavior in animal models of depression, and on cell survival and function in the CNS.

scholarly journals Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

2021 ◽  
Author(s):  
Pernille Bülow ◽  
Peter A Wenner ◽  
Victor Faundez ◽  
Gary J Bassell
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Neuronal Plasticity ◽  
Cortical Neurons ◽  
Initial Segment ◽  
Fragile X ◽  
Axon Initial Segment ◽  
Homeostatic Plasticity ◽  
Mitochondrial Morphology ◽  
And Function

Abstract Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and Fragile X Syndrome (FXS). In parallel, recent studies have uncovered important basic functions of mitochondria to power protein synthesis, synaptic plasticity and neuronal maturation. The mitochondrion also responds to neuronal activity by altering its morphology and function, and this plasticity of the mitochondrion appear important for proper neuronal plasticity. Previous research has reported disease induced changes in mitochondrial morphology and function, but it remains unknown how such abnormalities affect the ability of mitochondria to express activity dependent plasticity. This study addresses this gap in knowledge using a mouse model of FXS. We previously reported abnormalities in one type of homeostatic plasticity, called homeostatic intrinsic plasticity, which is known to involve structural changes in the axon initial segment (AIS). Another form of homeostatic plasticity, called synaptic scaling, which involves postsynaptic changes in dendrites, is also impaired in FXS. It remains unknown if or how homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment specific manner during homeostatic plasticity in cortical neurons from wild type mice, and that this plasticity-induced regulation is altered in Fmr1 KO neurons, as a model of FXS. We uncovered dendritic specific regulation of mitochondrial surface area, whereas AIS mitochondria show changes in polarity; both responses are lost in Fmr1 KO. Taken together our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS contributes to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

scholarly journals Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment Are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Pernille Bülow ◽  
Peter A. Wenner ◽  
Victor Faundez ◽  
Gary J. Bassell
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Cortical Neurons ◽  
Initial Segment ◽  
Fragile X ◽  
Axon Initial Segment ◽  
Homeostatic Plasticity ◽  
Mitochondrial Morphology ◽  
Specific Regulation ◽  
And Function

Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and fragile X syndrome (FXS). Mitochondria show plasticity in morphology and function in response to neuronal activity, and previous research has reported impairments in mitochondrial morphology and function in disease. We and others have previously reported abnormalities in distinct types of homeostatic plasticity in FXS. It remains unknown if or how activity deprivation triggering homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment-specific manner during homeostatic plasticity using a model of activity deprivation in cortical neurons from wild-type mice and that this plasticity-induced regulation is altered in Fmr1-knockout (KO) neurons. We uncovered dendrite-specific regulation of the mitochondrial surface area, whereas axon initial segment (AIS) mitochondria show changes in polarity; both responses are lost in the Fmr1 KO. Taken together, our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS could contribute to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

scholarly journals Typical and atypical brain development: a review of neuroimaging studies

2013 ◽  
Vol 15 (3) ◽  
pp. 359-384 ◽  
Keyword(s):  
Brain Development ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Early Adulthood ◽  
22Q11.2 Deletion Syndrome ◽  
Developmental Trajectory ◽  
Deletion Syndrome ◽  
Effective Interventions ◽  
And Function ◽  
The Brain

In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders.

scholarly journals Altered synaptic transmission and maturation of hippocampal CA1 neurons in a mouse model of human chr16p11.2 microdeletion

2018 ◽  
Vol 119 (3) ◽  
pp. 1005-1018 ◽  
Author(s):  
Hung-Chi Lu ◽  
Alea A. Mills ◽  
Di Tian
Keyword(s):  
Mouse Model ◽  
Synaptic Transmission ◽  
Neurodevelopmental Disorders ◽  
Synaptic Function ◽  
Glutamatergic Synapses ◽  
Ca1 Neurons ◽  
Hippocampal Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
And Function ◽  
Circuit Function

The pathophysiology of neurodevelopmental disorders is often observed early in infancy and toddlerhood. Mouse models of syndromic disorders have provided insight regarding mechanisms of action, but most studies have focused on characterization in juveniles and adults. Insight into developmental trajectories, particularly those related to circuit and synaptic function, will likely yield important information regarding disorder pathogenesis that leads to symptom progression. Chromosome 16p11.2 microdeletion is one of the most common copy number variations associated with a spectrum of neurodevelopmental disorders. Yet, how haploinsufficiency of chr16p11.2 affects early synaptic maturation and function is unknown. To address this knowledge gap, the present study focused on three key components of circuit formation and function, basal synaptic transmission, local circuit function, and maturation of glutamatergic synapses, in developing hippocampal CA1 neurons in a chr16p11.2 microdeletion mouse model. The data demonstrate increased excitability, imbalance in excitation and inhibition, and accelerated maturation of glutamatergic synapses in heterozygous deletion mutant CA1 neurons. Given the critical role of early synaptic development in shaping neuronal connectivity and circuitry formation, these newly identified synaptic abnormalities in chr16p11.2 microdeletion mice may contribute to altered developmental trajectory and function of the developing brain. NEW & NOTEWORTHY The synaptic pathophysiology underlying neurodevelopmental disorders often emerges during infancy and toddlerhood. Therefore, identifying initial changes in synaptic function is crucial for gaining a mechanistic understanding of the pathophysiology, which ultimately will facilitate the design of early interventions. Here, we investigated synaptic and local circuit properties of hippocampal CA1 neurons in a human chr16p11.2 microdeletion mouse model during early postnatal development (preweaning). The data demonstrate increased neuronal excitability, excitatory/inhibitory imbalance, and accelerated maturation of glutamatergic synapses. These perturbations in early hippocampal circuit function may underlie the early pathogenesis of the heterozygous chr16p11.2 microdeletion, which is often associated with epilepsy and intellectual disability.

scholarly journals Rethinking Intellectual Disability from Neuro- to Astro-Pathology

2020 ◽  
Vol 21 (23) ◽  
pp. 9039
Author(s):  
Álvaro Fernández-Blanco ◽  
Mara Dierssen
Keyword(s):  
Intellectual Disability ◽  
Learning And Memory ◽  
Cognitive Processes ◽  
Neurodevelopmental Disorders ◽  
Current Knowledge ◽  
Fragile X ◽  
Memory Function ◽  
Special Focus ◽  
Neuronal Communication ◽  
Neuronal Control

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome.

scholarly journals Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samantha T. Reyes ◽  
Robert M. J. Deacon ◽  
Scarlett G. Guo ◽  
Francisco J. Altimiras ◽  
Jessa B. Castillo ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Regional Distribution ◽  
Receptor Occupancy ◽  
Autism Spectrum ◽  
Contextual Fear Conditioning ◽  
Synaptic Function ◽  
Sigma 1 Receptor ◽  
Sigma 1

AbstractFragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer’s disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

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