NM  Vol.4 No.3 , September 2013
Unilateral Fimbria/Fornix Transection Prevents the Synaptoplastic Effect of Dehydroepiandrosterone in the Hippocampus of Female, but Not Male, Rats
Abstract: Dehydroepiandrosterone (DHEA), the most abundant adrenal androgen in primates, is also synthesized from cholesterol in the brain. Like testosterone, DHEA induces spine synapse formation in the hippocampus. In female rats, this response is blocked by co-administration of an inhibitor of aromatase, the enzyme responsible for estrogen biosynthesis. In males, by contrast, the hippocampal synaptic response to DHEA is unaffected by treatment with an aromatase inhibitor. We hypothesized that this sex difference might reflect differential dependence of the hippocampal responses on subcortical afferents from the basal forebrain. To test this hypothesis, we examined the effects of unilateral fimbria/ fornix transection (FFX) on DHEA-induced synapse formation in the cornu ammonis 1 (CA1) hippocampal subfield of gonadectomized female and male rats. In ovariectomized females, CA1 spine synapse density after DHEA treatment was reduced by more than 60% ipsilateral to FFX. In males, however, unilateral FFX transection had no effect on spine synapse density after DHEA treatment. These results suggest that sex differences in the dependence on local estrogen biosynthesis of the CA1 synaptic response to androgen may at least in part be the result of sex differences in the relative contributions of afferents to the hippocampus from the basal forebrain.
Cite this paper: A. Mendell, N. MacLusky and C. Leranth, "Unilateral Fimbria/Fornix Transection Prevents the Synaptoplastic Effect of Dehydroepiandrosterone in the Hippocampus of Female, but Not Male, Rats," Neuroscience and Medicine, Vol. 4 No. 3, 2013, pp. 134-139. doi: 10.4236/nm.2013.43021.

[1]   T. Hajszan, K. Szigeti-Buck, N. L. Sallam, J. Bober, A. Parducz, N. J. MacLusky, C. Leranth and R. S. Duman, “Effects of Estradiol on Learned Helplessness and Associated Remodeling of Hippocampal Spine Synapses in Female Rats,” Biological Psychiatry, Vol. 67, No. 2, 2010, pp. 168-174. doi:10.1016/j.biopsych.2009.08.017

[2]   C. Leranth, M. Shanabrough and T. L. Horvath, “Hormonal Regulation of Hippocampal Spine Synapse Density Involves Subcortical Mediation,” Neuroscience, Vol. 101, No. 2, 2000, pp. 349-356. doi:10.1016/S0306-4522(00)00369-9

[3]   C. S. Woolley, “Estrogen-mediated Structural and Functional Synaptic Plasticity in the Female Rat Hippocampus,” Hormones and Behavior, Vol. 34, No. 2, 1998, pp. 140-148. doi:10.1006/hbeh.1998.1466

[4]   C. S. Woolley and B. S. McEwen, “Estradiol Mediates Fluctuation in Hippocampal Synapse Density during the Estrous Cycle in the Adult Rat,” Journal of Neuroscience, Vol. 12, No. 7, 1992, pp. 2549-2554.

[5]   C. Leranth, T. Hajszan and N. J. MacLusky, “Androgens Increase Spine Synapse Density in the CA1 Hippocampal Subfield of Ovariectomized Female Rats,” Journal of Neuroscience, Vol. 24, No. 2, 2004, pp. 495-499. doi:10.1523/JNEUROSCI.4516-03.2004

[6]   C. Leranth, O. Petnehazy and N. J. MacLusky, “Gonadal Hormones Affect Spine Synaptic Density in the CA1 Hippocampal Subfield of Male Rats,” Journal of Neuroscience, Vol. 23, 2003, pp. 1588-1592.

[7]   S. G. Beck and R. J. Handa, “Dehydroepiandrosterone (DHEA): A Misunderstood Adrenal Hormone and Spinetingling Neurosteroid,” Endocrinology, Vol. 145, No. 3, 2004, pp. 1039-1041. doi:10.1210/en.2003-1703

[8]   F. Labrie, A. Belanger, L. Cusan, J. L. Gomez and B. Candas, “Marked Decline in Serum Concentrations of Adrenal C19 Sex Steroid Precursors and Conjugated Androgen Metabolites during Aging,” Journal of Clinical Endocrinology and Metabolism, Vol. 82, No. 8, 1997, pp. 2396-2402. doi:10.1210/jc.82.8.2396

[9]   E. E. Baulieu, “Steroid Hormones in the Brain: Several Mechanisms?” In: K. Fuxe, J. A. Gutafsson and L. Wetterberg, Eds., Steroid Hormone Regulation of the Brain, Pergamon Press, Oxford, 1981, pp. 3-14.

[10]   E. E. Baulieu and P. Robel, “Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulfate (DHEAS) as Neuroactive Neurosteroids,” Proceedings of the National Academy of Sciences of USA, Vol. 95, No. 8, 1998, pp. 4089-4091. doi:10.1073/pnas.95.8.4089

[11]   C. Le Goascogne, P. Robel, M. Gouézou, N. Sananès, E. E. Baulieu and M. Waterman, “Neurosteroids: Cytochrome P450scc in Rat Brain,” Science, Vol. 237, No. 4819, 1987, pp. 1212-1215. doi:10.1126/science.3306919

[12]   P. Zheng, “Neuroactive Steroid Regulation of Neurotransmitter Release in the CNS: Action, Mechanism and Possible Significance,” Progress in Neurobiology, Vol. 89, No. 2, 2009, pp. 134-152. doi:10.1016/j.pneurobio.2009.07.001

[13]   M. Vallee, W. Mayo and M. Le Moal, “Role of Pregnenolone, Dehydroepiandrosterone and Their Sulfate Esters on Learning and Memory in Cognitive Aging,” Brain Research Reviews, Vol. 37, No. 1-3, 2001, pp. 301-312. doi:10.1016/S0165-0173(01)00135-7

[14]   R. K. Sripeda, C. E. Marx, A. P. King, N. Rajaram, S. N. Garfinkel, J. L. Abelson and I. Liberzon, “DHEA Enhances Emotion Regulation Neurocircuits and Modulates Memory for Emotional Stimuli,” Neuropsychopharmacology. doi:10.1038/npp.2013.79

[15]   T. Hajszan, N. J. MacLusky and C. Leranth, “Dehydroepiandrosterone Increases Hippocampal Spine Synapse Density in Ovariectomized Female Rats,” Endocrinology, Vol. 145, No. 3, 2004, pp. 1042-1045. doi:10.1210/en.2003-1252

[16]   N. J. MacLusky, T. Hajszan and C. Leranth, “Effects of Dehydroepiandrosterone and Flutamide on Hippocampal CA1 Spine Synapse Density in Male and Female Rats: Implications for the Role of Androgens in Maintenance of Hippocampal Structure,” Endocrinology, Vol. 145, No. 9, 2004, pp. 4154-4161. doi:10.1210/en.2004-0477

[17]   E. G. Kovacs, N. J. MacLusky and C. Leranth, “Effects of Testosterone on Hippocampal CA1 Spine Synaptic Density in the Male Rat are Inhibited by Fimbria/Fornix Transection,” Neuroscience, Vol. 122, No. 3, 2003, pp. 807-810. doi:10.1016/j.neuroscience.2003.08.046

[18]   C. Leranth and M. Shanabrough, “Supramamillary Area Mediates Subcortical Estrogenic Action on Hippocampal Synaptic Plasticity,” Experimental Neurology, Vol. 167, No. 2, 2001, pp. 445-450. doi:10.1006/exnr.2000.7585

[19]   T. T. Lam and C. Leranth, “Role of the Medial Septum Diagonal Band of Broca Cholinergic Neurons in Oestrogen-Induced Spine Synapse Formation on Hippocampal CA1 Pyramidal Cells of Female Rats,” European Journal of Neuroscience, Vol. 17, No. 10, 2003, pp. 1997-2005. doi:10.1046/j.1460-9568.2003.02637.x

[20]   T. L. Horvath, L. Roa-Pena, R. L. Jakab, E. R. Simpson and F. Naftolin, “Aromatase in Axonal Processes of Early Postnatal Hypothalamic and Limbic Areas Including the Cingulate Cortex,” Journal of Steroid Biochemistry and Molecular Biology, Vol. 61, No. 3-6, 1997, pp. 349-357. doi:10.1016/S0960-0760(97)80032-5

[21]   D. A. Rusakov, H. A. Davies, E. Harrison, G. Diana, G. Richter-Levin, T. V. P. Bliss and M. G. Stewart, “Ultrastructural Synaptic Correlates of Spatial Learning in Rat Hippocampus,” Neuroscience, Vol. 80, No. 1, 1997, pp. 69-77. doi:10.1016/S0306-4522(97)00125-5

[22]   H. Braendgaard and H. J. Gundersen, “The Impact of Recent Stereological Advances on Quantitative Studies of the Nervous System,” Journal of Neuroscience Methods, Vol. 18, No. 1-2, 1986, pp. 39-78. doi:10.1016/0165-0270(86)90112-3

[23]   D. C. Sterio, “The Unbiased Estimation of Number and Sizes of Arbitrary Particles Using the Disector,” Journal of Microscopy, Vol. 134, No. 2, 1984, pp. 127-136. doi:10.1111/j.1365-2818.1984.tb02501.x

[24]   J. V. Small, “Measurement of Section Thickness,” In: D.S. Bocciarelli, Ed., Proceedings of the 4th European Conference on Electron Microscopy, Tipographia Poliglotta Vatican, Rome, 1968, pp. 609-610.

[25]   C. Leranth, M. Shanabrough and D. E. Redmond Jr., “Gonadal Hormones are Responsible for Maintaining the Integrity of Spine Synapses in the CA1 Hippocampal Subfield of Female Non-human Primates,” Journal of Comparative Neurology, Vol. 447, No. 1, 2002, pp. 34-42. doi:10.1002/cne.10230

[26]   C. Leranth, T. Hajszan, K. Szigeti-Buck, J. Bober and N. J. MacLusky, “Bisphenol A Prevents the Synaptogenic Response to Estradiol in Hippocampus and Prefrontal Cortex of Ovariectomized Nonhuman Primates,” Proceedings of the National Academy of Sciences, Vol. 105, No. 37, 2008, pp. 14187-14191. doi:10.1073/pnas.0806139105

[27]   M. I. Boulware, J. P. Weick, B. R. Becklund, S. P. Kuo, R. D. Groth and P. G. Mermelstein, “Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein,” Journal of Neuroscience, Vol. 25, No. 20, 2005, pp. 5066-5078. doi:10.1523/JNEUROSCI.1427-05.2005

[28]   M. I. Boulware, H. Kordasiewicz and P. G. Mermelstein, “Caveolin Proteins Are Essential for Distinct Effects of Membrane Estrogen Receptors in Neurons,” Journal of Neuroscience, Vol. 27, No. 37, 2007, pp. 9941-9950. doi:10.1523/JNEUROSCI.1647-07.2007

[29]   D. P. Srivastava, E. M. Waters, P. G. Mermelstein, E. A. Kramar, T. J. Shors and F. Liu, “Rapid Estrogen Signaling in the Brain: Implications for the Fine-Tuning of Neuronal Circuitry,” Journal of Neuroscience, Vol. 31, No. 35, 2011, pp. 16056-16063. doi:10.1523/JNEUROSCI.4097-11.2011

[30]   V. N. Luine, R. I. Khylchevskaya and B. S. McEwen, “Effect of Gonadal Steroids on Activities of Monoamine Oxidase and Choline Acetylase in Rat Brain,” Brain Research, Vol. 86, No. 2, 1975, pp. 293-306. doi:10.1016/0006-8993(75)90704-0

[31]   J. Meitzen, D. D. Grove and P. G. Mermelstein, “The Organizational and Aromatization Hypotheses Apply to Rapid, Nonclassical Hormone Action: Neonatal Masculinization Eliminates Rapid Estradiol Action in Female Hippocampal Neurons,” Endocrinology, Vol. 153, No. 10, 2012, pp. 4616-21. doi:10.1210/en.2012-1525

[32]   S. Sarkey, I. Azcoitia, L. M. Garcia-Segura, D. GarciaOvejero and L. L. DonCarlos, “Classical Androgen Receptors in Nonclassical Sites in the Brain,” Hormones and Behavior, Vol. 53, No. 5, 2008, pp. 753-764. doi:10.1016/j.yhbeh.2008.02.015

[33]   N. E. Tabori, L. S. Stewart, V. Znamensky, R. D. Romeo, S. E. Alves, B. S. McEwen and T. A. Milner, “Ultrastructural Evidence That Androgen Receptors Are Located at Extranuclear Sites in the Rat Hippocampal Formation,” Neuroscience, Vol. 130, No. 1, 2005, pp. 151-163. doi:10.1016/j.neuroscience.2004.08.048

[34]   Y. Xu, M. Tanaka, L. Chen and M. Sokabe, “DHEAS Induces Short-Term Potentiation via the Activation of a Metabotropic Glutamate Receptor in the Rat Hippocampus,” Hippocampus, Vol. 22, No. 4, 2012, pp. 707-722. doi:10.1002/hipo.20932