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Transcriptional response to amphetamine in Drosophila dopamine transporter (DAT) loss-of-function mutant

ABSTRACT: We used Drosophila genetic and behavioral models to examine AMPH-induced transcriptional changes in DAT-dependent manner, as those would be the most relevant to the stimulatory effects of the drug in the brain. We previously showed that flies respond to AMPH by increasing their locomotor activity and decreasing their sleep in a dopamine-dependent manner. Flies that carry a loss-of-function mutation in the gene encoding the Drosophila DAT homolog (dDATfmn, henceforth referred to as DAT mutants) exhibit heightened activity levels at baseline, consistent with increased levels of extracellular dopamine caused by the impairment of reuptake. In this study we compared gene expression changes in response to AMPH in brains of isogenic w1118 strain (WT) and DAT mutants. We found genes involved in the control of mRNA translation to be significantly upregulated in response to AMPH in a DAT-dependent manner.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE196162 | GEO | 2022/02/18

REPOSITORIES: GEO

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Project description:Oligo array analysis with bioinformatics tools identified genes with very high expression levels in the meninges, arachnoid and pial membranes, and associated vasculature (MAV) as potentially important and unique to these tissues in rat. It was also determined whether these genes were more sensitive to expression changes after a neurotoxic exposure to amphetamine (AMPH). Gene expression in the vascular rich MAV was compared to the neuronal rich tissues of the striatum and parietal cortex. In controls, 850 genes differed by more than 5-fold when comparing the MAV to both striatum and parietal cortex. Genes specifically identified with the blood-brain barrier (BBB) were also expressed at high levels indicating they may help form tight junctions in MAV. Genes with 15-fold or greater expression in MAV compared to striatum or cortex are of potential uniqueness and importance to MAV function. Many of the identified genes are abundant in different types of epithelial tissue and function in binding, transport or metabolize ions and solute, and may help MAV regulate cerebrospinal fluid. Many others with high expressions are involved in immune system function possibly serving to facilitate lymphocyte and macrophage trafficking in vasculature and cerebrospinal fluid. Expression in the MAV has similarities to the choroid plexus indicating considerable overlap in functions. Genes in MAV with a higher expression (relative to brain) were affected in greater numbers than expected by EIH and AMPH (SIGNIFICANT?). Many expression increases evoked by AMPH and EIH in MAV relate to reactive oxidative stress and inflammation. However, AMPH induced more robust alterations in the expression of genes related to ion/solute transport, lipid metabolism, bacterial infection and damage than EIH. The BBB-related genes Sox18 and Cldn5 expression decreased more with AMPH than EIH, and Cldn 9 and Esam were increase only by AMPH. It is not known how these changes affect BBB function and integrity. Gene expression patterns in MAV were compared to two regions of brain (striatum and parietal cortex) to identify genes important to MAV function and determine whether their expressions were sensitive to a neurotoxic exposure to amphetamine.

Project description:Oligo array analysis with bioinformatics tools identified genes with very high expression levels in the meninges, arachnoid and pial membranes, and associated vasculatures (MAV) which are potentially important and unique to these tissues functional capabilities in rat. It was also determined if these genes were more sensitive to expression changes after a neurotoxic exposure to environmentally induced hyperthermia (EIH) or amphetamine (AMPH). Gene expression in the MAV was compared to the neuronal rich tissues of the striatum and parietal cortex. In controls, 1,116 genes differed by more than 5-fold when comparing MAV to both striatum and parietal cortex. Genes specifically identified with the blood-brain barrier (BBB) were also expressed at high levels indicating they may help form tight junctions in MAV. The more than 300 genes having a 15-fold or greater expression in MAV compared to striatum and cortex were deemed of potential uniqueness and importance to MAV function. Many of these genes are abundant in different types of epithelial tissue and function in binding, transport or metabolism of ions and solute, and may help MAV regulate cerebrospinal fluid. Many others with high expressions are involved in immune system function possibly serving to facilitate lymphocyte and macrophage trafficking in vasculature and cerebrospinal fluid. Genes in MAV with a higher expression (relative to striatum and cortex) were affected in greater numbers than expected by EIH and AMPH. Many expression increases evoked by AMPH and EIH in MAV relate to reactive oxidative stress and inflammation. However, AMPH induced more robust alterations in the expression of genes related to ion/solute transport (Slc15a1), lipid metabolism (Fst), bacterial infection (Lbp) and oddly pancreatitis (Reg3a, Reg3b). Expression of the BBB-related genes Sox18 and Cldn5 decreased in all regions with AMPH and EIH but even more so in MAV. Esam increased with AMPH in all regions while Angpt2 was only affected in striatum and parietal cortex. It is not known how these changes affect MAV, striatum or parietal cortex tight junction function/BBB and integrity.

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Transcriptional response to amphetamine in Drosophila dopamine transporter (DAT) loss-of-function mutant

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