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Ethanol-Induced Changes in Brain of Transgenic Mice Overexpressing DYRK1A
Marta Fructuoso1,2, Yu Chen Gu3, Nadim Kassis3
1Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Pompeu Fabra University (Universitat Pompeu Fabra, UPF), 08003, Barcelona, Spain.
Abstract:
Alcoholism is a chronic relapsing disorder defined by loss of control over excessive consumption of ethanol despite damaging effects on the liver and brain. We previously showed that the overexpression in mice of Dyrk1A (TgDyrk1A, for dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A) reduces the severity of alcohol mediated liver injury. Ethanol consumption has also been associated with increased brain glutamate concentration that led to therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Interestingly, mice overexpressing Dyrk1A (TgDyrk1A mice) present a reduction of glutamatergic brain transmission, which we propose could be protective against alcohol intake. To answer this question, we investigated the ethanol preference in TgDyrk1A mice using a two-bottle choice paradigm. TgDyrk1A mice showed a non-significant decrease of voluntary ethanol intake and ethanol preference compared with wild-type mice. At the peripheral level, mice overexpressing Dyrk1A show lower ethanol plasma levels, indicating a faster ethanol metabolism. At the end of the protocol, lasting 21 days, brains were extracted for protein analysis. Ethanol reduced levels of the synaptic protein PSD-95 and increased the glutamate decarboxylase GAD65, specifically in the cortex of TgDyrk1A mice. Our results suggest that overexpression of DYRK1A may cause different ethanol-induced changes in the brain.
Insights
Overexpression of dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A (Dyrk1A) in mice did not significantly alter alcohol preference but did affect alcohol metabolism and brain responses. This suggests Dyrk1A influences how the brain processes alcohol.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Alcoholism is a complex disorder with significant liver and brain damage.
- Dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A (Dyrk1A) overexpression in mice previously reduced alcohol-induced liver injury.
- Ethanol consumption is linked to altered brain glutamate levels, a target for alcoholism therapies.
Purpose of the Study:
- To investigate the effect of Dyrk1A overexpression on ethanol preference and intake in mice.
- To explore the impact of Dyrk1A on ethanol metabolism and brain changes associated with alcohol consumption.
Main Methods:
- Utilized a two-bottle choice paradigm to assess voluntary ethanol intake and preference in Dyrk1A-overexpressing mice and wild-type controls.
- Measured plasma ethanol levels to evaluate ethanol metabolism.
- Analyzed brain protein levels, including PSD-95 and GAD65, in the cortex after chronic ethanol exposure.
Main Results:
- Dyrk1A-overexpressing mice showed a non-significant decrease in voluntary ethanol intake and preference.
- Mice overexpressing Dyrk1A exhibited lower plasma ethanol levels, suggesting faster metabolism.
- Ethanol exposure altered synaptic protein PSD-95 and glutamate decarboxylase GAD65 levels in the cortex of Dyrk1A mice.
Conclusions:
- Overexpression of Dyrk1A influences ethanol metabolism and induces distinct changes in brain proteins in response to ethanol.
- These findings suggest a potential role for Dyrk1A in modulating the brain's response to alcohol, warranting further investigation.
