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Androgen Effects on Hippocampal CA1 Spine Synapse Numbers Are Retained in Tfm Male Rats with Defective Androgen Receptors

Departments of Obstetrics, Gynecology and Reproductive Sciences (N.J.M., T.H., C.L.) and Neurobiology (C.L.), Yale University School of Medicine, New Haven, Connecticut 06520; Laboratory of Molecular Neurobiology (T.H.), Biological Research Center, Hungarian Academy of Sciences, 6726 Szeged, Hungary; Neuroscience Program (J.A.J., C.L.J.), Michigan State University, East Lansing, Michigan 48824; and Department of Biomedical Sciences (N.J.M.), University of Guelph, Guelph, Ontario, Canada N1G 2W1

Address all correspondence and requests for reprints to: Neil J. MacLusky, Ph.D., Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1. E-mail: nmaclusk{at}uoguelph.ca.

The effects of estradiol benzoate (EB), dihydrotestosterone (DHT), or the antiandrogen hydroxyflutamide on CA1 pyramidal cell dendritic spine synapses were investigated in adult male rats. To elucidate the contribution of the androgen receptor to the hormone-induced increase in hippocampal CA1 synapses, wild-type males were compared with males expressing the Tfm mutation, which results in synthesis of defective androgen receptors. Orchidectomized rats were treated with EB (10 µg/rat·d), DHT (500 µg/rat·d), hydroxyflutamide (5 mg/rat·d), or the sesame oil vehicle sc daily for 2 d and examined using quantitative electron microscopic stereological techniques, 48 h after the second injection. In wild-type males, DHT and hydroxyflutamide both induced increases in the number of spine synapses in the CA1 stratum radiatum, whereas EB had no effect. DHT almost doubled the number of synaptic contacts observed, whereas hydroxyflutamide increased synapse density by approximately 50%, compared with the vehicle-injected controls. Surprisingly, in Tfm males, the effects of EB, DHT, and hydroxyflutamide were all indistinguishable from those observed in wild-type animals. These observations demonstrate that Tfm male rats resemble normal males in having no detectable hippocampal synaptic response to a dose of EB that is highly effective in females. Despite the reduction in androgen sensitivity as a result of the Tfm mutation, hippocampal synaptic responses to both DHT and a mixed androgen agonist/antagonist (hydroxyflutamide) remain intact in Tfm males. These data are consistent with previous results suggesting that androgen effects on hippocampal spine synapses may involve novel androgen response mechanisms.

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