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McCarthy M.M., Wright C.L., Schwarz J.M., and Nugent B.M.

Department of Physiology and Program in Neuroscience, University of Maryland School of
Medicine, Baltimore MD 21201 USA, fax 410-706-8341,
This year marks the 50 anniversary of an iconic paper published in Endocrinology by William
Young and his trainees at the University of Kansas [1]. This elegant study of the enduring
consequences of hormonal treatment of pregnant guinea pigs, brought clarity to a disparate
collection of observations of hormonal effects on reproductive behavior. The authors proposed a
novel hypothesis, that early hormonal actions predisposed adult behavior, now codified as the
Organizational / Activational Hypothesis of hormonally mediated sexual differentiation of the
brain. The predictions stemming from this hypothesis have provided a sturdy framework against
which competing theories have, and continue to be tested, and as such as earned the moniker,
Sexual differentiation of the brain is a developmental process whereby gonadal steroids act during a
perinatal sensitive period on the undifferentiated neural substrate to permanently alter it so that
ultimately brain phenotype will match gonad phenotype. Central to the process of differentiation in
rats and mice is the conversion within neurons of testicularly derived testosterone to estradiol.
Treatment with testosterone, but not the nonaromatizable androgen dihydrotestosterone (DHT),
mimics many of the trophic effects of estradiol, and normal masculinization of the brain is
prevented subsequent to disruption of aromatase during the sensitive period [2, 3]. This basic
principle, that the male brain is masculinized by local conversion of estradiol, is elucidated by the
“aromatization hypothesis” first proposed by Naftolin in 1975 [4] and expanded on by others [5].
Stereotypic sexual behavior in rodents is an excellent example of an adult behavioral endpoint that
is organized by neonatal hormonal exposure. The medial nucleus of the POA is a major site
regulating male sexual behavior, whereas the VMN of the hypothalamus is required for the
expression of female sexual behavior [6]. Of particular interest here is how steroids exert an
organizational effect on developing cells in these brain regions. Males have two to three times more
dendritic spines and spine synapses in the neonatal POA and VMN than females, and both these sex
differences are dependent on early exposure to estradiol [2, 7]. A useful construct for investigating
mechanistic questions of sexual differentiation is the operationally defined and distinct processes of
masculinization, feminization and defeminization. Masculinization refers to an active
developmental process initiated by gonadal steroids during the perinatal sensitive period followed
by expression of normal male copulatory behavior in adulthood. Feminization is essentially what
happens in the absence of masculinization, meaning it is the default pathway leading to expression
of lordosis under the proper hormonal conditions in adulthood. Defeminization is distinct from but
occurs in tandem with masculinization and refers to the process whereby the ability to express
female sexual behavior is lost.
The amino acid glutamate is a fundamental building block of proteins as well as a dominant
excitatory neurotransmitter in the mammalian CNS. Its actions are generally rapid and mediated via
two varieties of ionotropic receptors, NMDA and AMPA, and a class of metabotropic G-protein
coupled receptors referred to as the mGluR. Because it is ubiquitous and so essentially
fundamental, glutamate has not generally been considered a reasonable candidate for mediating a
process as specific and selective as sexual differentiation of the brain, but we have recently
demonstrated that glutamate is critically involved in both masculinization and defeminization in the
POA and VMN, respectively.
In the POA, glutamate is a component of the actions of prostaglandin E2 (PGE2), as evidenced by
the ability of AMPA receptor antagonists to block the induction of dendritic spines by PGE2 [2].
Activation of AMPA receptor only partly accounts for PGE2 actions, however, while a role for
PKA is emerging (Wright & McCarthy, unpublished observation). In the VMN, estradiol binds to its cogent receptor and promotes the release of glutamate from presynaptic terminals, which in turn activates postsynaptic NMDA and AMPA receptors, leading to calcium influx, activation of MAP kinase and dendritic spine formation [8]. The enhanced glutamate release requires estradiol-induced activation of PI3 Kinase, and this occurs as rapidly as within one hour after steroid exposure. Neither the activation of PI3 Kinase nor the enhanced glutamate release by estradiol requires protein synthesis, but they do require the ER. [9]. These neuroanatomical results predict that neonatal glutamate administration should be sufficient to induce defeminization and blocking glutamate should disrupt estradiol-induced defeminization. Both of these predictions have proved true[8, 10]. However, there is also a positive effect of glutamate receptor activation on organization of male sexual behavior, suggesting a functional connection between the cellular events of masculinization and defeminization. This work was supported by NIH R01MH52716 to MMM. Reference list
1. Phoenix, C.H., et al., Organizing action of prenatally administered testosterone proprionate on the tissues mediating
mating behavior in the female guinea pig. Endocrinology, 1959. 65: p. 369-382. 2. Amateau, S.K. and M.M. McCarthy, A novel mechanism of dendritic spine plasticity involving estradiol induction of prostglandin-E2. J. Neurosci., 2002. 22: p. 8586-8596. 3. Bakker, J., et al., Sexual partner preference requires a functional aromatase (cyp19) gene in male mice. Horm 4. Naftolin, F., Ryan, K.J., Davies, I.J., Reddy, V.V., Flores, F., Petro, Z., Kuhn, M., White, R.J., Takaoka, Y., Wolin, L., The formation of estrogens by central neuroendocrine tissues. Recent Prog. Horm. Res., 1975. 31: p. 295-319. 5. McEwen, B.S., et al., Aromatization: Important for sexual differentiation of the neonatal rat brain. Hormones and 6. McCarthy, M.M., Estradiol and the developing brain. Physiol Rev, 2008. 88(1): p. 91-124. 7. Todd, B.J., et al., Glutamate AMPA/kainate receptors, not GABAA receptors, mediate estradiol-induced sex differences in the hypothalamus. . Developmental Neurobiology, 2007. 67: p. 304-315. 8. Schwarz, J.M., et al., Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: A mechanism for organizational sex differences. Neuron, 2008. 58: p. 584-598. 9. Schwarz, J.M. and M.M. McCarthy, The role of neonatal NMDA receptor activation in defeminization and masculinization of sex behavior in the rat. Horm Behav, 2008. 54: p. 662-668. 10. SCHWARZ, J.M. AND M.M. MCCARTHY, STEROID-INDUCED SEXUAL DIFFERENTIATION OF THE BRAIN: MULTIPLE PATHWAYS, ONE GOAL. J. NEUROCHEM., 2008. 105: P. 1561-1572.


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