Dataset Information

GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics.

ABSTRACT: Chronic consumption of alcohol by humans has been shown to lead to impairment of executive and cognitive functions. Here, we have studied the mRNA expression of ion channel receptors for glutamate and GABA in the dorsal striatum of post-mortem brains from alcoholics (n = 29) and normal controls (n = 29), with the focus on the caudate nucleus that is associated with the frontal cortex executive functions and automatic thinking and on the putamen area that is linked to motor cortices and automatic movements. The results obtained by qPCR assay revealed significant changes in the expression of specific excitatory ionotropic glutamate and inhibitory GABA-A receptor subunit genes in the caudate but not the putamen. Thus, in the caudate we found reduced levels of mRNAs encoding the GluN2A glutamate receptor and the ?, ?, and ?2 GABA-A receptor subunits, and increased levels of the mRNAs encoding GluD1, GluD2, and GABA-A ?1 subunits in the alcoholics as compared to controls. Interestingly in the controls, 11 glutamate and 5 GABA-A receptor genes were more prominently expressed in the caudate than the putamen (fold-increase varied from 1.24 to 2.91). Differences in gene expression patterns between the striatal regions may underlie differences in associated behavioral outputs. Our results suggest an altered balance between caudate-mediated voluntarily controlled and automatic behaviors in alcoholics, including diminished executive control on goal-directed alcohol-seeking behavior.

SUBMITTER: Bhandage AK

PROVIDER: S-EPMC4257153 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics.

Bhandage Amol K AK Jin Zhe Z Bazov Igor I Kononenko Olga O Bakalkin Georgy G Korpi Esa R ER Birnir Bryndis B

Frontiers in cellular neuroscience 20141205

Chronic consumption of alcohol by humans has been shown to lead to impairment of executive and cognitive functions. Here, we have studied the mRNA expression of ion channel receptors for glutamate and GABA in the dorsal striatum of post-mortem brains from alcoholics (n = 29) and normal controls (n = 29), with the focus on the caudate nucleus that is associated with the frontal cortex executive functions and automatic thinking and on the putamen area that is linked to motor cortices and automatic ...[more]

PMID: 25538565

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Project description:Background: Molecular adaptations in the striatum mediated by dopamine (DA) denervation or Levodopa (L-dopa) treatment have been implicated with the motor deficits found in Parkinsonâs disease (PD). Alterations in glutamatergic neurotransmission and anti-oxidant mechanisms are reported to play important roles in mediating these changes. However, the mechanisms mediating the molecular adaptations in the striatum are not well understood. In recent years, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of gene expression with fundamental roles in numerous biological processes. miRNAs are known to influence the development and maintenance of striatal neurons. To determine the contribution of miRNAs in molecular adaptations found in PD, we screened the expression of 800 miRNAs in postmortem striatum samples obtained from PD and neurologically normal controls. We detected the expression of approximately 250 miRNAs in postmortem human putamen samples collected from patients with PD and healthy controls. There was an abundance of a subset of 17 miRNAs (10 up- and 7 down-regulated) differing substantially between PD and the control, suggesting that miRNAs are altered in the striatum during the course of PD. Computational analysis show that many of these miRNAs targets pro-inflammatory factors in the striatum. Therefore, we sought to detrmine the expression of experimentally validated pro-inflammatory transcripts in PD striatum. Methods: Using a digital gene expression platform to quantify 134 gene transcripts, we compared human postmortem putamen tissues from patients with PD and neurologically normal controls. Results: We identified deregulated expression of 10 gene transcripts (4 up- and 6 down-regulated mRNAs) in postmortem human putamen samples collected fromPD patients compared to controls. The expression of these genes negative correlates with the expression of many of the differentially epxressed miRNAs. Moreover, many of these genes are predicted targets of the differentially expressed miRNAs. Conclusions: We identified deregulated mRNAs most likely associated with anti-oxidant mechanims in PD striatum. This approach may provide insights into pathogenesis of the disease. Human postmortem putamen tissues from 12 patients with PD symptoms and 12 neurologically normal controls were used in the study. Samples were obtained from the Human Brain and Spinal Fluid Resource Center, Los Angeles, CA through NIH NeuroBioBank, and stored at -80Â°C until RNA isolation. Total RNA was extracted using the mirVana RNA isolation kit, following the manufacturerâs instructions (Ambion). Using 225ng total RNA, mRNA levels were assayed by direct digital detection using Nanostring nCounter assay kits (Nanostring Technologies).

Project description:Background: Molecular adaptations in the striatum mediated by dopamine (DA) denervation or Levodopa (L-dopa) treatment have been implicated with the motor deficits found in Parkinson’s disease (PD). Alterations in glutamatergic neurotransmission and anti-oxidant mechanisms are reported to play important roles in mediating these changes. However, the mechanisms mediating the molecular adaptations in the striatum are not well understood. In recent years, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of gene expression with fundamental roles in numerous biological processes. miRNAs are known to influence the development and maintenance of striatal neurons. To determine the contribution of miRNAs in molecular adaptations found in PD, we screened the expression of 800 miRNAs in postmortem striatum samples obtained from PD and neurologically normal controls. We detected the expression of approximately 250 miRNAs in postmortem human putamen samples collected from patients with PD and healthy controls. There was an abundance of a subset of 17 miRNAs (10 up- and 7 down-regulated) differing substantially between PD and the control, suggesting that miRNAs are altered in the striatum during the course of PD. Computational analysis show that many of these miRNAs targets pro-inflammatory factors in the striatum. Therefore, we sought to detrmine the expression of experimentally validated pro-inflammatory transcripts in PD striatum. Methods: Using a digital gene expression platform to quantify 134 gene transcripts, we compared human postmortem putamen tissues from patients with PD and neurologically normal controls. Results: We identified deregulated expression of 10 gene transcripts (4 up- and 6 down-regulated mRNAs) in postmortem human putamen samples collected fromPD patients compared to controls. The expression of these genes negative correlates with the expression of many of the differentially epxressed miRNAs. Moreover, many of these genes are predicted targets of the differentially expressed miRNAs. Conclusions: We identified deregulated mRNAs most likely associated with anti-oxidant mechanims in PD striatum. This approach may provide insights into pathogenesis of the disease.

Dataset Information

GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics.

Publications

GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics.

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