Synaptic Scaling of Corticostriatal Circuits Underlies Hyperactivity in GABA Transporter-1 Deficient Mice
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PROVIDER: PRJNA870283 | ENA |
REPOSITORIES: ENA
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Project description:To explore the potential mediators of corticostriatal synaptic scaling in GAT1–/– mice, whole-tissue mRNA sequencing was carried out for the dorsal striatum of GAT1+/+ and GAT1–/– mice.
2022-08-20 | GSE211419 | GEO
Project description:Homeostatic synaptic scaling entails adjustment of synaptic strength on a cell to prolonged changes of neuronal activity, which is postulated to participate in neuropsychiatric disorders in vivo. Here, we find that sustained elevation in ambient GABA levels, by either genetic deletion or pharmacological blockade of GABA transporter-1 (GAT1), leads to synaptic scaling up of corticostriatal pathways, which underlies locomotor hyperactivity. Meanwhile, medium spiny neurons of the dorsal striatum exhibit an aberrant increase in excitatory synaptic transmission and corresponding structural changes in dendritic spines. Mechanistically, GAT1 deficiency dampens the expression and function of metabotropic glutamate receptors (mGluRs) and endocannabinoid (eCB)-dependent long-term depression of excitatory transmission. Conversely, restoring mGluR function in GAT1 deficient mice rescues excitatory transmission. Lastly, pharmacological potentiation of mGluR-eCB signaling or inhibition of homomeric-GluA1 AMPA receptors eliminates locomotor hyperactivity in the GAT1 deficient mice. Together, these results reveal a synaptic scaling mechanism in corticostriatal pathways that regulate locomotor activity.
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2021-11-09 | GSE159947 | GEO
Project description:GABA-receptive microglia selectively sculpt developing inhibitory circuits
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Project description:Homeostatic control of pyramidal neuron firing rate involves a functional balance of feedforward excitation and feedback inhibition in neocortical circuits. Here, we reveal a dynamic scaling in vesicular excitatory (vesicular glutamate transporters VGLUT1 and VGLUT2) and inhibitory (vesicular inhibitory amino acid transporter VIAAT) transporter mRNA and synaptic protein expression in rat neocortical neuronal cultures, using a well established in vitro protocol to induce homeostatic plasticity. During the second and third week of synaptic differentiation, the predominant vesicular transporters expressed in neocortical neurons, VGLUT1 and VIAAT, are both dramatically upregulated. In mature cultures, VGLUT1 and VIAAT exhibit bidirectional and opposite regulation by prolonged activity changes. Endogenous coregulation during development and homeostatic scaling of the expression of the transporters in functionally differentiated cultures may serve to control vesicular glutamate and GABA filling and adjust functional presynaptic excitatory/inhibitory balance. Unexpectedly, hyperexcitation in differentiated cultures triggers a striking increase in VGLUT2 mRNA and synaptic protein, whereas decreased excitation reduces levels. VGLUT2 mRNA and protein are expressed in subsets of VGLUT1-encoded neocortical neurons that we identify in primary cultures and in neocortex in situ and in vivo. After prolonged hyperexcitation, downregulation of VGLUT1/synaptophysin intensity ratios at most synapses is observed, whereas a subset of VGLUT1-containing boutons selectively increase the expression of VGLUT2. Bidirectional and opposite regulation of VGLUT1 and VGLUT2 by activity may serve as positive or negative feedback regulators for cortical synaptic transmission. Intracortical VGLUT1/VGLUT2 coexpressing neurons have the capacity to independently modulate the level of expression of either transporter at discrete synapses and therefore may serve as a plastic interface between subcortical thalamic input (VGLUT2) and cortical output (VGLUT1) neurons.
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Project description:Neural circuits utilize a host of homeostatic plasticity mechanisms, including synaptic scaling, to maintain stability in circuits undergoing experience-dependent remodeling necessary for information processing. During synaptic scaling, compensatory adaptations in synaptic strength are induced after chronic manipulations in neuronal firing, but our understanding of this process is largely limited to its initial induction. How these homeostatic synaptic adaptations evolve when activity renormalizes and their impact on subsequent homeostatic compensation are both poorly understood. To examine these issues, we investigated whether a previous history of homeostatic scaling in networks of cultured hippocampal neurons altered their subsequent homeostatic responses to chronic activity manipulations. Unexpectedly, we found that a history of synaptic scaling strongly suppressed future scaling to the same, and even opposite, activity challenges. This history-dependent suppression was specific for future homeostatic compensation, as networks with a prior scaling history showed no deficits in the chemical induction of long-term potentiation (cLTP), a Hebbian form of synaptic plasticity. Hippocampal neurons with a prior scaling history exhibited normal engagement of activity-dependent signaling during subsequent activity challenges (as assessed by examination of the ERK/MAPK pathway) but demonstrated widespread alterations in activity-dependent transcriptional
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Project description:We performed a microarray analysis of auditory midbrain (inferior colliculus, IC) mRNA from young adult CBA mice (controls) with good hearing, middle aged (MA) with good hearing, and old mild (MP) and severe (SP) presbycusic CBA mice. Fold Change data derived from RMA normalization revealed that the overall GABA receptor alpha 6 expression profiles for MA, MP and SP were down-regulated relative to young adult controls with good hearing. Relative real-time PCR for five GABA receptors confirmed this age-related down regulation quantitatively. Functional hearing data: Auditory Brainstem Responses (ABR) enriched the analysis to select the probe-sets that changed with age and hearing loss by the linear regression best-fit line model technique. GABA receptor genotype-phenotype correlations with auditory functional data indicated that GABA-receptor subtypes are under expressed in SP mice. Hierarchical clustering (HC) analyses yielded statistical significance of normalized GeneChip data Real-time PCR showed that Gabra6, GABA B receptor 1 (Gabbr1), and Gaba transporter protein Slc32a1 may be involved in physiological changes that occur in age-related hearing loss. Presbycusis – age-related hearing loss – is the number one communicative disorder of our aged population. In this study we analyzed gene expression for a set of GABA receptors in the inferior colliculus of aging CBA mice using the Affymetrix GeneChip MOE430A. Functional phenotypic hearing changes from RMA normalized microarray data (39 replicates) in four age-groups, Young Controls and Middle aged mice with good hearing, mild and sever e presbycusis from old mice. Fold change gene expression derived from RMA normalized data were first subjected to one-way ANOVA, and then linear regression was performed. The selected gene expression changes were confirmed by relative real-time relative to young adult controls with good hearing. Statistically significant and real time PCR confirmed GABA receptor genes; Gabra6, GABA B receptor 1 (Gabbr1), and Gaba transporter protein Slc32a1, may be involved in physiological changes that occur in age-related hearing loss. Lastly, gene expression measures of each age group were correlated with pathway/network relationships relevant to the inferior colliculus using Pathway Architect, to identify key pathways consistent with the gene expression changes observed In the study of Expression changes in IC GABA receptors in the Auditory Midbrain of young adult and aging presbycusis mice total of thirty nine chips were used. The normal aging mice were in Four groups Young adults Controls with good hearing (8 mice, 8 MOE430A GeneChips), Middle aged group with good hearing ( 17 mice, 17 MOE430A GeneChips), Mild Presbycusis with limited hearing loss (9 mice, 9 MOE430A GeneChips) and Severe Presbycusis (5 mice, 5 MOE430A GeneChips).
2013-08-06 | E-GEOD-49522 | biostudies-arrayexpress
Project description:Metabolic programs of immune cells are closely linked to their effector functions , where physiological molecules provide environmental cues and guidance. Exactly how it happens is still being unraveled. Insulin maintains normal blood glucose levels and glucose is themain source of energy and a precursor for many biomolecules in T cells, whereas γ-aminobutyric acid (GABA), best known as a neurotransmitter, is increasingly recognized as a regulatory molecule in the immune system. Here, we demonstrate that GABA-mediated reduction of metabolic activity and release of inflammatory molecules, including IFNγ and IL-10, was abolished in human CD4+ T cells, when the glucose concentration was elevated above normal levels. In a glucose concentration-dependent manner, insulin enhanced the GABAA receptors activated currents and GABA-dependent Ca2+ influx. GABA decreased, whereas insulin maintained glycolysis but in a SGLT (Na + -glucose transporter)-dependent manner, revealing expression of SGLTs in activated CD4+ T cells. The SGLTs antagonist phlorizin, alone or together with GABA, restored the inhibition of IFNγ and IL-10 release in presence of high glucose. This study exposes concerted effects of GABA, glucose and insulin on CD4+ T cells metabolic activity and release of inflammatory molecules, and identifies a role for SGLTs in CD4+ T cells function.
2024-08-10 | PXD041654 | Pride
Project description:Attention deficit hyperactivity disorder (ADHD) is a common psychiatric condition of children with a prevalence of 5-10% worldwide. Up to 30% of adults with a history of childhood ADHD maintain symptoms in later life; these adult ADHD patients are severely impaired in social and professional life due to persistence of ADHD core symptoms like impulsivity, attention deficit and hyperactivity as well as frequently observed co-morbidities like alcohol and drug abuse, major depression, bipolar and personality disorders. Pharmaceutical treatment options include methylphenidate (MPH), which is amongst others an inhibitor of the dopamine transporter and therefore increases dopamine levels in the brain. However, not all ADHD patients are MPH responders with clinical features to distinguish responders and non-responders being not at hand so far. Likewise, neurobiological reasons for drug response are still elusive. Here, we examined the global transcriptional response of MPH on lymphoblastoid cell lines (LCLs) derived from ADHD patients and unaffected controls.
2014-09-05 | E-GEOD-52889 | biostudies-arrayexpress
Project description:We performed a microarray analysis of auditory midbrain (inferior colliculus, IC) mRNA from young adult CBA mice (controls) with good hearing, middle aged (MA) with good hearing, and old mild (MP) and severe (SP) presbycusic CBA mice. Fold Change data derived from RMA normalization revealed that the overall GABA receptor alpha 6 expression profiles for MA, MP and SP were down-regulated relative to young adult controls with good hearing. Relative real-time PCR for five GABA receptors confirmed this age-related down regulation quantitatively. Functional hearing data: Auditory Brainstem Responses (ABR) enriched the analysis to select the probe-sets that changed with age and hearing loss by the linear regression best-fit line model technique. GABA receptor genotype-phenotype correlations with auditory functional data indicated that GABA-receptor subtypes are under expressed in SP mice. Hierarchical clustering (HC) analyses yielded statistical significance of normalized GeneChip data Real-time PCR showed that Gabra6, GABA B receptor 1 (Gabbr1), and Gaba transporter protein Slc32a1 may be involved in physiological changes that occur in age-related hearing loss. Presbycusis – age-related hearing loss – is the number one communicative disorder of our aged population. In this study we analyzed gene expression for a set of GABA receptors in the inferior colliculus of aging CBA mice using the Affymetrix GeneChip MOE430A. Functional phenotypic hearing changes from RMA normalized microarray data (39 replicates) in four age-groups, Young Controls and Middle aged mice with good hearing, mild and sever e presbycusis from old mice. Fold change gene expression derived from RMA normalized data were first subjected to one-way ANOVA, and then linear regression was performed. The selected gene expression changes were confirmed by relative real-time relative to young adult controls with good hearing. Statistically significant and real time PCR confirmed GABA receptor genes; Gabra6, GABA B receptor 1 (Gabbr1), and Gaba transporter protein Slc32a1, may be involved in physiological changes that occur in age-related hearing loss. Lastly, gene expression measures of each age group were correlated with pathway/network relationships relevant to the inferior colliculus using Pathway Architect, to identify key pathways consistent with the gene expression changes observed
2013-08-06 | GSE49522 | GEO