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J. Biol. Chem., Vol. 282, Issue 10, 7352-7359, March 9, 2007

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AKT and CDK5/p35 Mediate Brain-derived Neurotrophic Factor Induction of DARPP-32 in Medium Size Spiny Neurons in Vitro^*

Alexey Bogush, Steve Pedrini, Joshua Pelta-Heller, Tung Chan, Qian Yang^¶, Zixu Mao^¶, Emily Sluzas, Tracy Gieringer, and Michelle E. Ehrlich¹

From the Farber Institute for Neurosciences and Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, Center for Translational Research, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and the ^¶Department of Pharmacology and Neurology, Emory University School of Medicine, Atlanta, Georgia 30322

Mature striatal medium size spiny neurons express the dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa (DARPP-32), but little is known about the mechanisms regulating its levels or the specification of fully differentiated neuronal subtypes. Cell extrinsic molecules that increase DARPP-32 mRNA and/or protein levels include brain-derived neurotrophic factor (BDNF), retinoic acid, and estrogen. DARPP-32 induction by BDNF in vitro requires phosphatidylinositide 3-kinase (PI3K), but inhibition of phosphorylation of protein kinase B/Akt does not entirely abolish expression of DARPP-32. Moreover, the requirement for Akt has not been established. Using pharmacologic inhibitors of PI3K, Akt, and cyclin-dependent kinase 5 (cdk5) and constitutively active and dominant negative PI3K, Akt, cdk5, and p35 viruses in cultured striatal neurons, we measured BDNF-induced levels of DARPP-32 protein and/or mRNA. We demonstrated that both the PI3K/Akt/mammalian target of rapamycin and the cdk5/p35 signal transduction pathways contribute to the induction of DARPP-32 protein levels by BDNF and that the effects are on both the transcriptional and translational levels. It also appears that PI3K is upstream of cdk5/p35, and its activation can lead to an increase in p35 protein levels. These data support the presence of multiple signal transduction pathways mediating expression of DARPP-32 in vitro, including a novel, important pathway via by which PI3K regulates the contribution of cdk5/p35.

Received for publication, July 10, 2006 , and in revised form, December 26, 2006.

^* This work was supported by National Institutes of Health Grants R01NS045942 (to M. E. E.), R01NS048254, and AG023695 (to X. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 900 Walnut St., JHN 411, Philadelphia, PA 19107. Tel.: 215-955-1484; Fax: 215-503-4358; E-mail: Michelle.Ehrlich{at}jefferson.edu.

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