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Effects of Diras2-knockdown in murine hippocampal primary cells

ABSTRACT: Attention-deficit / hyperactivity disorder (ADHD) is a clinically heterogeneous childhood behavioral neurodevelopmental disorder which is highly persistent into adulthood and shows an heritability up to 80%. In previous studies, our group delineated the 9q22 region by both linkage studies and genome-wide association studies as a candidate locus for ADHD. This region harbors the DIRAS2 (MIM: 607863) gene which is coding for a Ras GTPase. To get more knowledge about the role of Diras2 in the brain, an adeno-associated virus (AAV) was used for a short hairpin RNA (shRNA) induced knock-down of Diras2 gene expression in mouse hippocampal primary cells. To identify possible targets of Diras2 and signalling cascades in which Diras2 might play a role, GeneChip Mouse Gene 2.0 ST Arrays (Affymetrix) were used for expression profiling of the RNA samples.

ORGANISM(S): Mus musculus

PROVIDER: GSE66432 | GEO | 2018/12/01

REPOSITORIES: GEO

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Project description:Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines.

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Effects of Diras2-knockdown in murine hippocampal primary cells

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