Gene network analysis reveals a role for striatal glutamatergic receptors in dysregulated risk-assessment behavior of autism mouse models
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PROVIDER: PRJNA576268 | ENA |
REPOSITORIES: ENA
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Project description:Autism Spectrum Disorder (ASD) presents a wide, and often varied, behavioral phenotype. Impulsivity and improper assessment of risks has been widely reported among individuals diagnosed with ASD. However, there is little knowledge of the molecular underpinnings of the impaired risk-assessment phenotype. In this study, we have identified impaired risk-assessment activity in multiple male ASD mouse models. By performing network-based analysis of striatal whole transcriptome data from each of these ASD models, we have identified a cluster of glutamate receptor–associated genes that correlate with the risk-assessment phenotype. Furthermore, pharmacological inhibition of striatal glutamatergic receptors was able to mimic the dysregulation in risk-assessment. Therefore, this study has identified a molecular mechanism that may underlie impulsivity and risk-assessment dysregulation in ASD.
2019-10-08 | GSE138539 | GEO
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Project description:Mutations in PARK15, which encodes for the F-box protein FBXO7 have been associated with Parkinsonian Pyramidal syndrome, a rare and complex movement disorder with Parkinsonian symptoms, pyramidal tract signs and juvenile onset. Our previous study showed that systemic loss of Fbxo7 in mice causes motor defects and premature death. We have also demonstrated that FBXO7 has a crucial role in neurons as the specific deletion in tyrosine hydroxylase-positive or glutamatergic forebrain neurons leads to late-onset or early-onset motor dysfunction, respectively. In this study, we examined NEXCre; Fbxo7fl/fl mice, in which Fbxo7 was specifically deleted in glutamatergic projection neurons. The effects of FBXO7 deficiency on striatal integrity were investigated with HPLC and histological analyses. NEX-Cre;Fbxo7fl/fl mice revealed an increase in striatal dopamine concentrations, changes in the glutamatergic, GABAergic and dopaminergic pathways, astrogliosis and microgliosis and little or no neuronal loss in the striatum. To determine the effects on the integrity of the synapse, we purified synaptic membranes, subjected them to quantitative mass spectrometry analysis and found alterations in the complement system, endocytosis and exocytosis pathways. These neuropathological changes coincide with alterations in spontaneous home cage behavior. Taken together, our findings suggest that FBXO7 is crucial for corticostriatal projections and the synaptic integrity of the striatum, and consequently for proper motor control.
2023-09-18 | PXD044119 | Pride
Project description:Stereotypic behavior (SB) is common in emotional stress-involved psychiatric disorders and is often attributed to glutamatergic impairments, but the underlying mechanisms are unknown. To challenge the causal involvement of cholinergic neuromodulation in SB, we studied TgR mice with impaired cholinergic transmission due to over-expression of the stress-inducible soluble ‘readthrough’ acetylcholinesterase-R (AChE-R) variant. RNA-sequencing revealed 37 differentially expressed microRNAs in TgR mice hippocampi, 8 of which targeting over 5 human cholinergic-related transcripts each. Further, microarray tests of TgR prefrontal cortices displayed up to 428 long RNA transcripts differentially expressed from those of FVB/N mice, primarily glutamatergic-related mRNA transcripts (P<1x10-3). Suggesting behavioral relevance, TgR brains presented c-fos over-expression at motor behavior-regulating brain regions and immune-labeled AChE-R excess in SB-regulating basal ganglia, limbic brain nuclei and the brain stem. Compatible with this, TgR mice showed impaired organization of behavior, performance errors in a serial maze test, escape-like locomotion and less rearing under changed environmental familiarity/novelty conditions. Our findings attribute stress-induced SB to previously unknown microRNA-mediated perturbation of cholinergic/glutamatergic networks, support malfunctioning hierarchical control of cholinergic signaling as impairing the behavioral inhibitory regulation via glutamatergic neuromodulation and underscore new therapeutic strategies for correcting stereotypic behaviors.
2023-01-21 | GSE144022 | GEO
Project description:Astrocytes tile the central nervous system, but their functions in neural microcircuits in vivo and their roles in mammalian behavior remain incompletely defined. We used 2-photon laser scanning microscopy (2PLSM), electrophysiology, MINIscopes, RNA-seq and a new genetic approach to characterize the effects of reduced striatal astrocyte Ca2+ signaling in vivo. In wild type mice, reducing striatal astrocyte Ca2+-dependent signaling increased repetitive self-grooming behaviors by altering medium spiny neuron (MSN) activity. The mechanism involved astrocyte-mediated neuromodulation mediated by ambient GABA and was corrected by blocking astrocyte GABA transporter 3 (GAT-3). Furthermore, in a mouse model of Huntington’s disease, dysregulation of GABA and astrocyte Ca2+ signaling accompanied excessive self-grooming, which was relieved by blocking GAT-3. Assessments with RNA-seq revealed astrocyte genes and pathways regulated by Ca2+ signaling in a cell autonomous and non-cell autonomous manner, including Rab11a, a regulator of GAT-3 functional expression. Thus, striatal astrocytes contribute to neuromodulation controlling obsessive-compulsive-like behavior in mice.
2019-05-09 | GSE114755 | GEO
Project description:Astrocytes tile the central nervous system, but their functions in neural microcircuits in vivo and their roles in mammalian behavior remain incompletely defined. We used 2-photon laser scanning microscopy (2PLSM), electrophysiology, MINIscopes, RNA-seq and a new genetic approach to characterize the effects of reduced striatal astrocyte Ca2+ signaling in vivo. In wild type mice, reducing striatal astrocyte Ca2+-dependent signaling increased repetitive self-grooming behaviors by altering medium spiny neuron (MSN) activity. The mechanism involved astrocyte-mediated neuromodulation mediated by ambient GABA and was corrected by blocking astrocyte GABA transporter 3 (GAT-3). Furthermore, in a mouse model of Huntington’s disease, dysregulation of GABA and astrocyte Ca2+ signaling accompanied excessive self-grooming, which was relieved by blocking GAT-3. Assessments with RNA-seq revealed astrocyte genes and pathways regulated by Ca2+ signaling in a cell autonomous and non-cell autonomous manner, including Rab11a, a regulator of GAT-3 functional expression. Thus, striatal astrocytes contribute to neuromodulation controlling obsessive-compulsive-like behavior in mice.
2019-05-09 | GSE114756 | GEO
Project description:The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is Fragile X syndrome (FXS), an NDD caused by the dysfunctional RNA binding protein FMRP. Here we demonstrate how the brain region-specific composition of post-synaptic density (PSD) contributes to FXS. The FXS mouse model shows, in the striatum, an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, that is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.
2023-06-08 | PXD040331 | Pride
Project description:Gene expression profiles of glutamatergic neuron progenitors (Neurod6-positive cells)
2012-12-08 | E-MTAB-893 | biostudies-arrayexpress
Project description:Cell replacement strategies of affected cells have been performed in clinical studies of Parkinson´s disease with variable outcome. Conversion of endogenous glial cells into functional neurons might represent a more reliable alternative, thus here we developed a knock-in mouse line carrying a dual dCas9 transactivator system (dCAM), which allowed the conditional activation of the endogenous genes Ascl1, Lmx1a, and Nr4a2 in striatal astrocytes in vivo by delivering sgRNAs specific for their endogenous loci. In order to move this successful approach toward translation, we established an AAV based activator system carrying intein-split-dCas9-VP64, SAM (AAV-dCAS) activators, and the specific sgRNAs targeting transcription factor combinations. Both systems, the dCAM and the AAV-dCAS approach were successful in reprogramming of striatal astrocytes into GABAergic neurons, which functionally integrate into striatal circuits as evidenced by the alleviation of specific motor behaviors in a 6-OHDA Parkinson’s disease model. Thus, the AAV-dCAS approach may enable clinical therapies for Parkinson´s disease by reprogramming striatal astrocytes.
2022-03-15 | GSE149872 | GEO
Project description: Not available
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