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The Journal of Neuroscience, February 11, 2009, 29(6):1897-1903; doi:10.1523/JNEUROSCI.4647-08.2009

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Behavioral/Systems/Cognitive
Viral Vector-Mediated Overexpression of Estrogen Receptor- in Striatum Enhances the Estradiol-Induced Motor Activity in Female Rats and Estradiol-Modulated GABA Release

Kristin N. Schultz,² Silke A. von Esenwein,^6,7 Ming Hu,¹ Amy L. Bennett,⁸ Robert T. Kennedy,^2,3 Sergei Musatov,⁹ C. Dominique Toran-Allerand,^10,11 Michael G. Kaplitt,¹² Larry J. Young,^6,13 and Jill B. Becker^1,4,5

¹Molecular and Behavioral Neuroscience Institute and Departments of ²Chemistry, ³Pharmacology, ⁴Psychology, and ⁵Psychiatry, University of Michigan, Ann Arbor, Michigan 48109, ⁶Center for Behavioral Neuroscience and ⁷Psychology Department, Emory University, Atlanta, Georgia 30322, ⁸Department of Psychology, Towson University, Towson, Maryland 21252, ⁹Neurologix, Inc., Fort Lee, New Jersey 07024, Departments of ¹⁰Anatomy and Cell Biology and ¹¹Neurology, Columbia University College of Physicians and Surgeons, New York, New York 10027, ¹²Department of Neurological Surgery, Weill Medical College of Cornell University, New York, New York 10065, and ¹³Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30322

Correspondence should be addressed to Dr. Jill B. Becker, Molecular and Behavioral Neuroscience Institute, 205 Zina Pitcher Place, Ann Arbor, MI 48109. Email: jbbecker{at}umich.edu

Classical estrogen receptor-signaling mechanisms involve estradiol binding to intracellular nuclear receptors [estrogen receptor- (ER) and estrogen receptor-β (ERβ)] to promote changes in protein expression. Estradiol can also exert effects within seconds to minutes, however, a timescale incongruent with genomic signaling. In the brain, estradiol rapidly potentiates stimulated dopamine release in the striatum of female rats and enhances spontaneous rotational behavior. Furthermore, estradiol rapidly attenuates the K⁺-evoked increase of GABA in dialysate. We hypothesize that these rapid effects of estradiol in the striatum are mediated by ER located on the membrane of medium spiny GABAergic neurons. This experiment examined whether overexpression of ER in the striatum would enhance the effect of estradiol on rotational behavior and the K⁺-evoked increase in GABA in dialysate. Ovariectomized female rats were tested for rotational behavior or underwent microdialysis experiments after unilateral intrastriatal injections of a recombinant adeno-associated virus (AAV) containing the human ER cDNA (AAV.ER) into the striatum; controls received either the same vector into areas outside the striatum or an AAV containing the human alkaline phosphatase gene into the striatum (AAV.ALP). Animals that received AAV.ER in the striatum exhibited significantly greater estradiol-induced contralateral rotations compared with controls and exhibited behavioral sensitization of contralateral rotations induced by a low-dose of amphetamine. ER overexpression also enhanced the inhibitory effect of estradiol on K⁺-evoked GABA release suggesting that disinhibition of dopamine release from terminals in the striatum resulted in the enhanced rotational behavior.

Key words: estradiol; dopamine; rotational behavior; microdialysis; striatum; adeno-associated viral vector; estrogen receptor

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Received Sept. 27, 2008; revised Dec. 16, 2008; accepted Jan. 4, 2009.

Correspondence should be addressed to Dr. Jill B. Becker, Molecular and Behavioral Neuroscience Institute, 205 Zina Pitcher Place, Ann Arbor, MI 48109. Email: jbbecker{at}umich.edu

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