Differential gene expression in the striatum of mice with very low expression of the vesicular monoamine transporter type 2 gene

• Published in: Brain research 2007-06, Vol.1152, p.10-16
• Main Authors: Colebrooke, R.E, Chan, P.M, Lynch, P.J, Mooslehner, K, Emson, P.C
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry and metabolism; Biological and medical sciences; Central nervous system; Corpus Striatum - metabolism; CREB; Cyclic AMP Response Element-Binding Protein - biosynthesis; Cyclic AMP Response Element-Binding Protein - genetics; Disease Models, Animal; Dopamine receptor; Dynorphin; Enkephalin; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Expression Profiling; In Situ Hybridization; Mice; Mice, Inbred C57BL; Neurology; Neuropeptides - biosynthesis; Neuropeptides - genetics; Parkinson's disease; Parkinsonian Disorders - genetics; Polymerase Chain Reaction; Proto-Oncogene Proteins c-fos - biosynthesis; Proto-Oncogene Proteins c-fos - genetics; Receptors, Dopamine D1 - biosynthesis; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D2 - biosynthesis; Receptors, Dopamine D2 - genetics; RNA, Messenger - biosynthesis; Substance P; Vertebrates: nervous system and sense organs; Vesicular Monoamine Transport Proteins - biosynthesis; Vesicular Monoamine Transport Proteins - genetics
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2007.03.032

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.