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The Journal of Neuroscience, January 28, 2004, 24(4):791-796; doi:10.1523/JNEUROSCI.3493-03.2004

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BRIEF COMMUNICATION
CRE-Mediated Transcription Is Increased in Huntington's Disease Transgenic Mice

Karl Obrietan¹ and Kari R. Hoyt²

¹Department of Neuroscience and ²Division of Pharmacology, The Ohio State University, Columbus, Ohio 43210

Disruption of cAMP response element (CRE)-dependent transcription has been hypothesized to contribute to neuronal death and dysfunction in Huntington's disease (HD) and other polyglutamine repeat disorders. Whether dysregulation of CRE-dependent transcription actually occurs in vivo in response to expression of expanded polyglutamine repeats has not been tested. We directly tested whether CRE-dependent transcription is affected in vivo by cross breeding a transgenic mouse model of HD (line R6/2) with a transgenic mouse that expresses a CRE-regulated reporter gene. Instead of compromised CRE-dependent transcription in HD mice, we found a robust upregulation of CRE-dependent transcription in several brain regions (striatum, hippocampus, cortex). CRE-mediated transcription was also evoked by striatal forskolin infusion and by photic stimulation in HD animals. Increased cAMP response element-binding protein (CREB) phosphorylation and elevated levels of the CREB-regulated gene product, CCAAT/enhancer binding protein , were also found in HD mice. Significant alterations in CREB binding protein expression and localization were not observed in symptomatic R6/2 mice. Thus, rather than repressing CRE-mediated transcription, mutant huntingtin appears to facilitate transcription via a CRE-dependent mechanism in vivo.

Key words: Huntington's disease; polyglutamine; transcription; CREB; CBP; transgenic

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Received July 25, 2003; revised November 26, 2003; accepted December 1, 2003.

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