Differential gene expression in the striatum of mice with very low expression of the vesicular monoamine transporter type 2 gene
Abstract The vesicular monoamine transporter type 2 (VMAT2) packages pre-synaptic monoamines into vesicles. Previously, we generated mice hypomorphic for the VMAT2 gene ( Slc18a2 ), which results in a ∼ 95% reduction in VMAT2 protein, disrupted vesicular storage, severe depletion of striatal dopamin...
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Published in | Brain research Vol. 1152; pp. 10 - 16 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
London
Elsevier B.V
04.06.2007
Amsterdam Elsevier New York, NY |
Subjects | |
Online Access | Get full text |
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Summary: | Abstract The vesicular monoamine transporter type 2 (VMAT2) packages pre-synaptic monoamines into vesicles. Previously, we generated mice hypomorphic for the VMAT2 gene ( Slc18a2 ), which results in a ∼ 95% reduction in VMAT2 protein, disrupted vesicular storage, severe depletion of striatal dopamine and mice with moderate motor behaviour deficits. Dopamine released from mid-brain dopamine neurons acts on post-synaptic type 1 (D1) and 2 (D2) receptors located on striatal medium spiny neurons to initiate a signalling cascade that leads to altered transcription factor activity, gene expression and neuronal activity. We investigated striatal gene expression changes in VMAT2hypo mice by quantitative real-time PCR and in situ hybridisation. Despite unaltered expression of D1 and D2 dopamine receptors, there were dramatic alterations in striatal mRNAs encoding the neuropeptides substance P, dynorphin, enkephalin and cholecystokinin. The promoters of these genes are regulated by a combination of transcription factors that includes cAMP responsive element binding protein-1 (CREB) and c-Fos. Indeed, the changes in peptide mRNAs were associated with elevated expression of Creb1 and c-Fos . These data indicate that striatal dopamine depletion, as a consequence of deficient vesicular storage in this mouse, triggers a complex program of gene expression, consistent with this mouse being an excellent model of Parkinson's disease. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0006-8993 1872-6240 |
DOI: | 10.1016/j.brainres.2007.03.032 |