Role of microRNAs in regulation of neuronal response to the neurotransmitter dopamine
Final Report Abstract
The goal of this proposal was to address the role of the recently discovered potent family of translational regulators, so called miRNAs, in maintenance and function of postnatal neurons in the central nervous system. Using a genetic approach that allowed postnatal, neuron-specific deletion of the miRNA-generating enzyme Dicer in Purkinje cells in the cerebellum and Dopamine 2 receptor (D2) expressing neurons in the striatum, we discovered that miRNAs are essential for postnatal neuronal survival. Ablation of Dicer in postnatal neurons is accompanied by a gradual and asynchronous loss of all miRNAs and leads to the development of a slow neurodegenerative death of the affected neurons. Purkinje cell specific ablation of Dicer leads to the development of ataxia, whereas D2-neuron specific ablation of Dicer is accompanied by the development of a Huntington’s disease-like behavioral phenotype. These data, published in the Journal of Experimental Medicine in 2007, demonstrate that miRNAs are essential for neuronal cell survival in different brain regions and raises the possibility of an involvement of miRNAs in neurodegenerative disorders. Furthermore, these data suggest that changes in individual miRNAs might play a major role in regulation of specific neuronal functions in these cells. To further address the potential role of individual miRNAs in striatal neuronal function, we investigated changes in the miRNA expression levels and pattern in response to dopamine, one of the major neurotransmitters in the brain. Since it is well established that treatment with psychostimulating drugs such as cocaine leads to a dramatic increase of dopamine levels in the brain, we analyzed miRNA expression changes in mice that have been acutely or chronically treated with cocaine. In summary, we identified a specific group of miRNAs that changes their expression levels and patterns in respond to a cocaine-induced increase in the neurotransmitter dopamine in the striatum. These results suggest a potential role of the specific cocaine-regulated miRNAs in striatal function and the development of drug addiction. To test the functional significance of these miRNAs in regulation of striatal function and the development of cocaine addiction, we generated mice with either a conditional deletion or a Cre-inducible overexpression of specific cocaine-induced miRNAs. We would predict that deletion and/or overexpression of these specific miRNAs in the striatum might affect the normal function of striatal neurons and play a role in the development of cocaine addiction. We are currently testing this hypothesis by analyzing striatum specific behavioral changes in these mice at the basal level and in response to acute and chronic cocaine treatment.
Publications
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Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med 2007, Vol. 204, No. 7, 1553-1558
Schaefer A, O’Carroll D, Lek Tan C, Hillman D, Sugimori M, Llinas R, and Greengard P
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A Translational Profiling Approach for the Molecular Characterization of CNS Cell Types. Cell 2008,135(4):738-48
Heiman M, Schaefer A, Gong S, Peterson J, Day M, Ramsey K, Suarez-Farina M, Schwarz C, Stephan D, Surmeier J, Greengard P, and Heintz N
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Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron. 2009 Dec 10;64(5):678-91
Schaefer A, Sampath SC, Intrator A, Min A, Gertler TS, Surmeier DJ, Tarakhovsky A, Greengard P
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Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science. 2010 Jan 8;327(5962):213-6
Maze I, Covington HE 3rd, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ, Ren Y, Sampath SC, Hurd YL, Greengard P, Tarakhovsky A, Schaefer A, Nestler EJ
