Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Haploinsufficiency in bromodomain containing 2 (Brd2) gene remodels synaptic transmission in female mouse striatum in a sex-specific manner

ABSTRACT: Our previous work showed that Brd2+/- mouse models the sex specific characteristics of juvenile myoclonic epilepsy, a subsyndrome of idiopathic generalized epilepsy. Here, we investigated a role of Brd2 gene in modulating the genomic fabrics responsible for the glutamatergic, GABAergic, dopaminergic, cholinergic and serotonergic transmission in the striatum of female mice. Agilent two-color gene expression arrays and the genomic fabric paradigm were used to determine whether the expression and networking of genes involved in the synaptic transmission differ between Brd2+/- and wildtype mice and whether these differences are sex-specific. As in Brd+/- male mice we found relatively few regulated genes in Brd2+/-female mice with respect to their wildtype counterparts. However, most of the regulated genes were directly related to control of anxiety and seizures, justifying the role of Brd2 upstream control of these traits. Remarkably, the sets of regulated genes in the two sexes did not overlap, supporting the conclusion of sex-specific control of traits by Brd2. Agilent mouse two-color gene expression arrays to profile striata of the prefrontal cortices of wildtype (W) and Brd2+/- (H) mouse female (F) adult C57Bl/6j mice. Differently labeled biological replicates were cohybridized with each array. Results of similarly labeled different conditions were compared then averaged for the two fluorescent labels. For instance: FW1 & FW3 were compared with FH1 & FH3, FW2 & FW4 were compared with FH2 & + FH4, and the results of the comparisons averaged. This design uses 100% of the resources, has a better normlaiztion and allows all possible comparisons among the conditions.

ORGANISM(S): Mus musculus

SUBMITTER: Dumitru Iacobas

PROVIDER: E-GEOD-72563 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We profiled the whole transcriptomes of female rat hypothalamic arcuate nuclei to determine the remodeling of the genomic fabrics responsible for the glutamatergic, GABAergic, dopaminergic, cholinergic and serotonergic transmission in epilepsy and recovery following different treatments. The rats were prenatally exposed (G15) to betamethasone (or just saline for control) followed by repeated adiministration of N-Methyl-D-Aspartic acid (NMDA) on postnatal days 12, 13 and 15 which triggered infantile spasms. Pups were treated with either ATCH, PMX53 (a potent C5ar1 antagonist) or saline to act as a control, on days 13, 14 and 15 prior to NMDA administration to determine what effects each treatment had on transcriptome recovery. Our Genomic Fabric Paradigm (GFP) is proposed as a transformative research approach to enhance the understanding of the brain transcriptomic alterations in epileptic rats and recovery following various treatments. The genomic fabric of a particular synapse is the structured transcriptome associated with the most interconnected and stably expressed gene network responsible for that type of neurotransmission. GFP refines the description of functional pathways by selecting the most prominent genes and determining their networking. Moreover, it quantifies the remodeling of functional pathways and their interplay in disease and recovery in response to a treatment. We found that priming with betamethasone had substantial consequences on the topology of the genomic fabrics of all kind of synaptic transmission and that NMDA-induced spasms strongly exacerbated the remodeling of these fabrics. Contrary to our findings in male rats, neither ACTH or PMX53 treatment recovered the normal synaptic transcriptomes. One tissue (hypothalamic arcuate nucleus) x two prenatal exposures (B = betamethasone, S = saline) x two conditions for the betamethasone expossed rats (with (Y) without (N) infantile spasms) x three postnatal treatments (A = ACTH, P = PMX53, S = saline) x one sex (M) . Biological replicates: 4 ASNSM, 4 ABNSM, 4 ABYSM, 4 ABYAM, 4 ABYPM. Please note that a the multiple yellow strategy has been adopted, in which differently labeled biological replicas are cohybridized, similarly labeled samples of distinct conditions are compared and the results of the green and red comparisons are averaged.

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Haploinsufficiency in bromodomain containing 2 (Brd2) gene remodels synaptic transmission in female mouse striatum in a sex-specific manner

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