Astrocytes in fragile X syndrome.

Astrocytes have an important role in neuronal maturation and synapse function in the brain. The interplay between astrocytes and neurons is found to be altered in many neurodevelopmental disorders, including fragile X syndrome (FXS) that is the most common inherited cause of intellectual disability and autism spectrum disorder. Transcriptional, functional, and metabolic alterations in knockout mouse astrocytes, human FXS stem cell-derived astrocytes as well as in models suggest autonomous effects of astrocytes in the neurobiology of FXS.

An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis.

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes.

Reduced expression in transcriptome of human iPSC-derived neural progenitors modeling fragile X syndrome.

Lack of FMR1 protein results in fragile X syndrome (FXS), which is the most common inherited intellectual disability syndrome and serves as an excellent model disease to study molecular mechanisms resulting in neuropsychiatric comorbidities. We compared the transcriptomes of human neural progenitors (NPCs) generated from patient-derived induced pluripotent stem cells (iPSCs) of three FXS and three control male donors. Altered expression of and in FXS NPCs suggested changes related to triplet repeat instability, RNA splicing, testes development, and pathways previously shown to be affected in FXS.

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome.

The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix.

Increased iron content in the heart of the Fmr1 knockout mouse.

Trace elements have important functions in several processes involved in cellular homeostasis and survival. Dysfunctional metal ion homeostasis can make an important impact on cellular defence mechanisms. We assessed the concentrations of 23 trace minerals in different tissues (brain, spleen, heart and liver) of Fmr1 knockout (KO) mice that display the main phenotype of Fragile X syndrome (FXS), an intellectual disability syndrome and the best-known monogenic model of autism spectrum disorder (ASD).

Generation of the Human Pluripotent Stem-Cell-Derived Astrocyte Model with Forebrain Identity.

Astrocytes form functionally and morphologically distinct populations of cells with brain-region-specific properties. Human pluripotent stem cells (hPSCs) offer possibilities to generate astroglia for studies investigating mechanisms governing the emergence of astrocytic diversity. We established a method to generate human astrocytes from hPSCs with forebrain patterning and final specification with ciliary neurotrophic factor (CNTF).

Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment.

FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS.

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome.

A triplet repeat expansion leading to transcriptional silencing of the gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele.

Modeling FXS with Mouse Neural Progenitors.

The neurosphere assay is a widely used method to culture neural precursor cells (NPCs), which include mixed populations of neural stem and progenitor cells, from the mammalian central nervous system. Fmr1-knockout (KO) mice generated to model fragile X syndrome (FXS) recapitulate the major phenotype of FXS. Neurosphere differentiation of cortical progenitors derived from brains of Fmr1-KO mice has been shown to reflect disordered mechanisms during cortical development in FXS in vivo.

Beneficial Effects of GLP-1 Agonist in a Male With Compulsive Food-Related Behavior Associated With Autism.

Individuals with autism spectrum disorder (ASD) frequently display intensely repetitive, restricted thoughts, and behaviors. These behaviors have similarities to compulsions and/or obsessions in obsessive compulsive disorder (OCD) and are primarily treated with behaviourally-based interventions and serotonin uptake inhibitors (SSRIs). Due to the lack of treatment responses in many cases, however, new treatments are being sought.

Astrocytes in Neuropathologies Affecting the Frontal Cortex.

To an increasing extent, astrocytes are connected with various neuropathologies. Astrocytes comprise of a heterogeneous population of cells with region- and species-specific properties. The frontal cortex exhibits high levels of plasticity that is required for high cognitive functions and memory making this region especially susceptible to damage.

Dysregulated Ca-Permeable AMPA Receptor Signaling in Neural Progenitors Modeling Fragile X Syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that represents a common cause of intellectual disability and is a variant of autism spectrum disorder (ASD). Studies that have searched for similarities in syndromic and non-syndromic forms of ASD have paid special attention to alterations of maturation and function of glutamatergic synapses. Copy number variations (CNVs) in the loci containing genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) subunits are associated with ASD in genetic studies.

Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein.

The absence of FMR1 protein (FMRP) causes fragile X syndrome (FXS) and disturbed FMRP function is implicated in several forms of human psychopathology. We show that intracellular calcium responses to depolarization are augmented in neural progenitors derived from human induced pluripotent stem cells and mouse brain with FXS. Increased calcium influx via nifedipine-sensitive voltage-gated calcium (Ca) channels contributes to the exaggerated responses to depolarization and type 1 metabotropic glutamate receptor activation.

Functional changes of AMPA responses in human induced pluripotent stem cell-derived neural progenitors in fragile X syndrome.

Altered neuronal network formation and function involving dysregulated excitatory and inhibitory circuits are associated with fragile X syndrome (FXS). We examined functional maturation of the excitatory transmission system in FXS by investigating the response of FXS patient-derived neural progenitor cells to the glutamate analog (AMPA). Neural progenitors derived from induced pluripotent stem cell (iPSC) lines generated from boys with FXS had augmented intracellular Ca responses to AMPA and kainate that were mediated by Ca-permeable AMPA receptors (CP-AMPARs) lacking the GluA2 subunit.

Epileptic Electroencephalography Profile Associates with Attention Problems in Children with Fragile X Syndrome: Review and Case Series.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and a variant of autism spectrum disorder (ASD). The FXS population is quite heterogeneous with respect to comorbidities, which implies the need for a personalized medicine approach, relying on biomarkers or endophenotypes to guide treatment. There is evidence that quantitative electroencephalography (EEG) endophenotype-guided treatments can support increased clinical benefit by considering the patient's neurophysiological profile.

Metabotropic glutamate receptor 5 responses dictate differentiation of neural progenitors to NMDA-responsive cells in fragile X syndrome.

Disrupted metabotropic glutamate receptor 5 (mGluR5) signaling is implicated in many neuropsychiatric disorders, including autism spectrum disorder, found in fragile X syndrome (FXS). Here we report that intracellular calcium responses to the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) are augmented, and calcium-dependent mGluR5-mediated mechanisms alter the differentiation of neural progenitors in neurospheres derived from human induced pluripotent FXS stem cells and the brains of mouse model of FXS. Treatment with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) prevents an abnormal clustering of DHPG-responsive cells that are responsive to activation of ionotropic receptors in mouse FXS neurospheres.

Cortical neurogenesis in fragile X syndrome.

The absence of fragile X mental retardation 1 protein (FMRP) results in fragile X syndrome (FXS) that is a common cause of intellectual disability and a variant of autism spectrum disorder. There is evidence that FMRP is involved in neurogenesis. FMRP is widely expressed throughout the embryonic brain development and its expression levels increases during neuronal differentiation.

Distinctive behavioral and cellular responses to fluoxetine in the mouse model for Fragile X syndrome.

Fluoxetine is used as a therapeutic agent for autism spectrum disorder (ASD), including Fragile X syndrome (FXS). The treatment often associates with disruptive behaviors such as agitation and disinhibited behaviors in FXS. To identify mechanisms that increase the risk to poor treatment outcome, we investigated the behavioral and cellular effects of fluoxetine on adult Fmr1 knockout (KO) mice, a mouse model for FXS.

Tissue plasminogen activator contributes to alterations of neuronal migration and activity-dependent responses in fragile X mice.

Fragile X syndrome (FXS) is the most common inherited neurodevelopmental disorder with intellectual disability. Here, we show that the expression of tissue plasminogen activator (tPA) is increased in glial cells differentiated from neural progenitors of Fmr1 knock-out mice, a mouse model for FXS, and that tPA is involved in the altered migration and differentiation of these progenitors lacking FMR1 protein (FMRP). When tPA function is blocked with an antibody, enhanced migration of doublecortin-immunoreactive neurons in 1 d differentiated FMRP-deficient neurospheres is normalized.

BDNF in fragile X syndrome.

Fragile X syndrome (FXS) is a monogenic disorder that is caused by the absence of FMR1 protein (FMRP). FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function underlying cognitive impairment, autism, and behavioral disturbance. Abnormalities in dendritic spines and synaptic transmission in the brain of FXS individuals and mouse models for FXS indicate perturbations in the development, maintenance, and plasticity of neuronal network connectivity.

Effect of glutamate receptor antagonists on migrating neural progenitor cells.

Neurotransmitters such as glutamate are potential regulators of neurogenesis. Interference with defined glutamate receptor subtypes affects proliferation, migration and differentiation of neural progenitor cells. The cellular targets for the actions of different glutamate receptor ligands are less well known.

Role of low voltage activated calcium channels in neuritogenesis and active migration of embryonic neural progenitor cells.

The central role of calcium influx and electrical activity in embryonic development raises important questions about the role and regulation of voltage-dependent calcium influx. Using cultured neural progenitor cell (NPC) preparations, we recorded barium currents through voltage-activated channels using the whole-cell configuration of the patch-clamp technique and monitored intracellular free calcium concentrations with Fura-2 digital imaging. We found that NPCs as well as expressing high-voltage-activated (HVA) calcium channels express functional low-threshold voltage-dependent calcium channels in the very early stages of differentiation (5 h to 1 day).

Neural stem cells.

Neural stem/progenitor cell (NPC) cultures are a tool to study the differentiation of neuronal cells and can be used to model disease conditions in studies investigating the pathological mechanisms affecting the development and cellular plasticity of the central nervous system. There is evidence that abnormalities of NPCs and their differentiation contribute to the pathophysiology of fragile X syndrome. The results obtained with NPC cultures derived from human and mouse brain tissue with the fragile X mutation are in line with the abnormalities of Fmr1-knockout mouse brain in vivo indicating that NPC cultures can be useful as a model for fragile X syndrome.

BDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse.

Fragile X syndrome (FXS) is a common cause of inherited mental retardation and the best characterized form of autistic spectrum disorders. FXS is caused by the loss of functional fragile X mental retardation protein (FMRP), which leads to abnormalities in the differentiation of neural progenitor cells (NPCs) and in the development of dendritic spines and neuronal circuits. Brain-derived neurotrophic factor (BDNF) and its TrkB receptors play a central role in neuronal maturation and plasticity.