Biology of Reproduction 67, 691-698 (2002)
© 2002 Society for the Study of Reproduction, Inc.
Steroid Modulation of Astrocytes in the Neonatal Brain: Implications for Adult Reproductive Function
Margaret M. McCarthy1,,a,b,
Stuart K. Amateaub, and
Jessica A. Mongc
a Department of Physiology
b Program in Neuroscience, University of Maryland, Baltimore, Maryland 21201
c Laboratory of Behavioral Neuroendocrinology, Rockefeller University, New York, New York 10021
 |
ABSTRACT
|
|---|
There is a growing appreciation for the importance of astrocytes, a type of nonneuronal glial cell, to overall brain functioning. The ability of astrocytes to respond to gonadal steroid hormones with changes in morphology has been well documented in the adult brain. It is also apparent that astrocytes of the developing brain are permanently differentiated by the neonatal hormonal milieu, in particular by estradiol, resulting in sexually dimorphic cell morphology, synaptic patterning, and density in males and females. The mechanisms of hormonally mediated astrocyte differentiation are likely to be region specific. In the arcuate nucleus of the hypothalamus, neuron-to-astrocyte signaling appears to play a critical role in estradiol-induced astrocyte differentiation during the first few days of life. Gamma aminobutyric acid (GABA) is an amino acid neurotransmitter that is synthesized and released exclusively by neurons. The levels of GABA are increased in the arcuate nucleus of neonatal males versus females. Preventing the increase in males or mimicking GABA action in females modulates astrocytes accordingly. Speculation about and evidence in support of the functional significance of this dimorphism to adult reproductive functioning is the topic of this review.
estradiol, hypothalamus, male reproductive tract, steroid hormones, testosterone
|
INTRODUCTION
|
|---|
Astrocytes are a subset of glial cell found throughout the brain. They are characterized by a high expression of glial fibrillary-associated protein (GFAP) at maturity and can have highly complex morphologies. In some brain regions, these cells are sensitive to gonadal steroid hormones and change their shape in response to the hormonal milieu, presumably to help in the coordination of brain, pituitary, and gonadal function. This involvement begins early in life and lasts throughout adulthood. One of the challenges facing neuroendocrinology is to elucidate the cellular and molecular mechanisms by which astrocytes participate in the control of reproductive functioning.
|
STEROID-MEDIATED DIFFERENTIATION OF THE NEONATAL BRAIN
|
|---|
In mammals, genetic sex is determined by the SRY gene located on the male Y chromosome. Expression of the highly conserved SRY gene initiates a cascade of events resulting in the differentiation of the bipotential gonad into the testis. In the absence of SRY expression, migrating germ cells develop into progenitor cells of the female ovary [1]. Consequent to gonadal development is the hormonal differentiation of the genitalia and ultimate establishment of secondary sex characteristics. Less well recognized is that the brain also begins life as bipotential, capable of assuming a male or female phenotype in equal measure. Distinct from the development of the gonads, however, differentiation of the brain is primarily a hormonally mediated event. Sex differences in hormonal profile are manifest prenatally, continue into the postnatal period, and are a function of the gonads. As a result, the perinatal period is characterized by dramatic sex differences in circulating gonadal steroids in a variety of mammalian species, including humans [2, 3].
Experimentally, the rat offers an excellent opportunity to investigate the relationship between steroid hormone action, brain morphology, and reproductive function. The profile of hormonal changes in the developing rat is well characterized. On Embryonic Day 18, the male testes secrete adult levels of testosterone that gradually decline until the occurrence of a second peak on the day of birth. In females, the ovary is quiescent, and exposure to gonadal steroids therefore remains uniform and low until puberty [4]. This dimorphic exposure to steroids has profound and permanent effects on the developing brain. In the rodent, it is well established that estradiol, the product of aromatizable testosterone, mediates most aspects of sexual differentiation during a restricted developmentally sensitive period. In rats, this sensitive period is operationally defined by the onset of testicular secretion on Embryonic Day 18 and is terminated when females become refractory to the masculinizing effects of exogenous testosterone (or estradiol). The termination of the sensitive period is variable for different functional endpoints and ranges from Postnatal Day 6 to Postnatal Day 10 [5]. The sexual phenotype of the rodent brain is critical to reproduction in that it enables both the expression of an ovulation-inducing surge of gonadotropin (LH) from the pituitary as well as the display of appropriate sexual behavior (mounting and thrusting in males, lordosis in females). The control of LH release is secondary to the activity of GnRH neurons, which are distributed in a diffuse fashion throughout the preoptic area and bed nucleus of the stria terminalis. The majority of GnRH neurons project to the median eminence and release their peptide into the portal vasculature to gain access to the anterior pituitary and induce LH release [6]. While control of LH release is directly attributable to the GnRH neurons, modulatory influences are exerted by afferent input [7], in particular GABAergic (where GABA is gamma aminobutyric acid) input from interneurons [8, 9]. Afferent input can also be modulated by adjacent glial cells. The arcuate nucleus is located just above the median eminence, and astrocytes in this brain region play a central role in synaptic plasticity across the estrus cycle, a function relevant to the LH surge on proestrus (see [10] for a review). The medial nucleus of the preoptic area is a major site regulating male sexual behavior, whereas the ventromedial nucleus of the hypothalamus is required for the expression of female sexual behavior (see [11, 12] for reviews). Each of these brain regions is a target of steroid hormone action in both the developing and adult brain. Of particular interest here is how steroids exert an organizational effect on developing cells in these brain regions, resulting in permanent morphologic changes that underlie adult sex differences in behavior and physiology.
|
ASTROCYTES ARE TARGETS OF STEROID-MEDIATED DIFFERENTIATION
|
|---|
Astrocytes are the most numerous and enigmatic subtype of glia, a broad categorization applied to all nonneuronal cells in the brain other than epithelium. Glia include reactive and protoplasmic astrocytes, oligodendrocytes, and microglia. Neuronal-glial interactions within the central nervous system (CNS) begin during early stages of fetal development and extend throughout the life span, with glia playing different roles at different stages. During neurogenesis and early development, radial glia provide scaffolding for migrating neurons [13] and can give rise to neurons themselves [14]. More often, the radial glia serve as the precursors to mature astrocytes, one category of which is the protoplasmic astrocyte. A hallmark of astrocyte maturation is increased stellation and synthesis of GFAP [15], an intermediate filament protein that is readily visible by immunocytochemistry.
Astrocytes have traditionally been viewed as secondary to neurons, acting as support cells or scavengers of metabolic waste and excess neurotransmitter. As appreciation for the importance of astrocytes has grown; so has awareness that these cells behave in a regionally specific manner. Astrocytes of one brain region express unique complements of signaling molecules that are exclusively relevant to local neurons [16–18]. Furthermore, hormonal modulation of astrocytes is region specific. One of the first and most prominent examples of hormonal modulation of astrocyte morphology is in the arcuate nucleus of the adult female rat. The amount of surface area covered by astrocytic processes changes dramatically across the estrous cycle, and this modification regulates the density of inhibitory GABAergic synapses [19]. Evidence suggests this phasic synaptic remodeling involves physical changes in astrocyte morphology and modulates the surge in LH release at proestrus [20]. Naturally occurring changes in astrocyte morphology across the cycle are mimicked by exogenous estradiol administration to ovariectomized rats [21–23], implicating this gonadal steroid as the mediator of this process.
Estradiol is also central to the sexual differentiation of arcuate astrocytes in the developing brain. Beginning as early as the day of birth and continuing throughout life, males exhibit more stellate astrocytes with longer processes and increased branching [24]. Neonatal administration of testosterone or estradiol, but not the nonaromatizable androgen dihydrotestosterone, to females results in an astrocyte morphology indistinguishable from that of gonadally intact males [25] (Fig. 1). A sex difference in astrocyte morphology of similar type and degree is observed in the preoptic area [26] but is notably lacking in the ventromedial nucleus of the hypothalamus [27]. All three of these brain regions, the arcuate, the preoptic area, and the ventromedial nucleus, express high levels of estrogen receptors and are involved in distinct but related aspects of reproductive behavior and physiology.
View larger version (37K):
[in this window]
[in a new window]
|
FIG. 1. Astrocytes in the developing arcuate nucleus are sexually dimorphic. An arbitrary categorization scheme was used to quantify the magnitude of differentiation of individual astrocytes. Class I astrocytes are relatively simple, with a bipolar morphology. The complexity of astrocytes increases progressively toward class IV, which is characterized by astrocytes with long branching processes, resulting in a stellate morphology. The frequency of astrocytes in each class was determined in the arcuate nucleus of Postnatal Day 3 pups. Intact males had significantly more class IV astrocytes than in any other class and more than unmanipulated (intact) females. Females that had been treated with estradiol (E2; 100 µg) for the 2 days prior to assay had a profile of astrocyte complexity that was indistinguishable from that of unmanipulated males. These data suggest that aromatization of testicular androgens to estrogens in the brain mediates the sex difference in astrocyte morphology (redrawn from original data presented in [25])
|
|
|
ASTROCYTIC AND NEURONAL MORPHOLOGY ARE RELATED
|
|---|
Ultimately, changes in astrocyte morphology must translate into changes in neuronal functioning if they are to be of relevance to reproduction. Synapse number is influenced by astrocytes [28], but establishing general principles of an astrocytic/neuronal morphologic relationship has proven elusive due to regional heterogeneity. For example, in the arcuate nucleus, increased astrocyte complexity is inversely correlated with the density of axo-dendritic spine synapses [27, 29]. In the newborn preoptic area, males also exhibit more complex astrocytes but, in contrast with the arcuate, appear to have increased dendritic spines [30]. In the ventromedial nucleus, there is no relationship between astrocyte complexity and dendritic spine density. While there is no modulation of astrocytes by estradiol in this brain region reported to date, estradiol increases the branching of neurites during the first few days of life [27]. Thus, the mechanisms regulating both astrocytic and neuronal morphology appear to be unique for each brain region and require further study. Nonetheless, we are beginning to further our understanding of hormonally responsive astrocytes in the developing brain and their impact on adult reproductive functioning.
|
CELLULAR MECHANISMS OF STEROID MODULATION OF ASTROCYTIC AND NEURONAL MORPHOLOGY
|
|---|
In the mature hypothalamus, GABA and glutamate are important mediators of neuronal communication. In general, GABA is predominantly inhibitory and counterbalances the excitatory drive of the glutamate system. GABA is synthesized exclusively in neurons from glutamate via the rate-limiting enzyme glutamic acid decarboxylase (GAD), which is present in two isozymes, GAD65 and GAD67 [31]. GAD65 is preferentially localized to neuron terminals, whereas GAD67 is distributed throughout the neuron [32]. There is a complex interrelationship between GABAergic modulation of gonadal steroid-induced events and gonadal steroid modulation of the GABAergic system. In adult brains, GABAergic neurotransmission in the ventromedial nucleus of the hypothalamus facilitates female sex behavior [33, 34], while GABA in the medial preoptic area is inhibitory to sex behavior in both females [34] and males [35]. In addition, GABA is implicated in the control of estrogen-mediated gonadotropin release [36–38]. Gonadal steroids modulate the adult GABAergic system through the regulation of GAD expression, and these changes in GAD mRNA are positively correlated with changes in GABA levels and GABA turnover [39, 40]. Recent studies implicate the GABAergic system as a mediator of sexual differentiation of the rodent brain during early postnatal development. There is a basic sex difference in the mRNA content for GAD and in GABA levels in several hypothalamic nuclei, including the neonatal arcuate nucleus. Masculinized brains exhibit higher levels of both GAD mRNA and GABA compared with feminized brains [41, 42]. More important, a divergence in the signal transduction responses of newborn males and females to GABAA receptor activation provides a mechanism for sexually dimorphic neuronal development [43].
Astrocytes throughout the brain are exquisitely sensitive to changes in their environmental milieu. They express a host of functional neurotransmitter receptors, including GABAA receptors [44–47] which are heteromeric pentamers permeable to chloride [48, 49]. In mature neurons, the reversal potential for chloride is negative to the resting membrane potential. Opening of the GABAA receptor constitutes the basis of most synaptic inhibition in the brain by allowing chloride influx and subsequent hyperpolarization of the membrane. However, in astrocytes, the reversal potential for chloride is positive to the resting membrane potential, and activation of these GABAA receptors has the opposite effect, i.e., depolarization of the astrocytic membrane. In astrocytes, activation of the GABAA receptor and subsequent membrane depolarization is of sufficient magnitude to activate voltage-dependent Ca2+ channels, resulting in a transient increase in intracellular Ca2+ concentration [45, 50]. Evidence suggests that neuronal activity also regulates astrocyte function and physiology since astrocyte differentiation is both blocked by bicuculline, a GABAA receptor antagonist, and induced in the absence of neurons if exposed to GABA or muscimol, a GABAA agonist. Baclofen, a GABAB receptor agonist, has no effect on astrocyte morphology, suggesting that GABA mediates astrocyte differentiation exclusively through its ionotropic receptor [51]. Astrocyte differentiation refers to the process of establishing the morphology of an astrocyte as stellate with multiple branching processes or as relatively bipolar with few primary processes that bifurcate infrequently. Differentiation is determined early in development. Astrocyte maturation, on the other hand, is evidenced by the expression of GFAP and is a process that begins early and continues throughout life.
Both GABA release and GABAA receptor activation are detected in hypothalamic neurons during late embryonic and early postnatal development. As previously mentioned, the neonatal GABAergic system is sensitive to the hormonal milieu such that males and masculinized females exhibit higher levels of both GAD mRNA and GABA in various loci, including the arcuate nucleus [41, 52]. During the same developmental period, astrocytes in the arcuate nucleus are becoming differentiated and sexually dimorphic such that arcuate astrocytes in masculinized brains are morphologically more complex (increased number of processes with increased length and more frequent branching) than arcuate astrocytes in feminized brains (see Fig. 1). To date, the presence of estrogen receptors in the astrocytes of the neonatal rat arcuate have not been demonstrated (reviewed in [25]), leading to the question of how estrogen mediates changes in arcuate astrocyte morphology. Based on the observation that estrogen receptors are present in the neurons of the neonatal rat arcuate [53], including GABAergic neurons [54], and given that neonatal males exhibit higher levels of GABA, we hypothesized that gonadal steroid-induced astrocyte differentiation is mediated through neuronally released GABA. Our recent in vivo analysis indicates that GABAergic signaling is a necessary component of gonadal steroid-induced astrocyte differentiation. When GAD65 and GAD67 protein levels in the neonatal hypothalamus were reduced with intrahypothalamic administration of antisense oligodeoxynucleotides to GAD mRNA, the gonadal steroid-induced masculinization of astrocytes in the arcuate was completely blocked during the first few days of life. The GAD antisense oligodeoxynucleotides had no effect on astrocytes in the intact female arcuate. Conversely, muscimol administered to newborn females induced astrocyte differentiation in the absence of exogenous steroids (Fig. 2). We have interpreted these results to indicate that steroid-induced astrocyte differentiation in the neonatal arcuate of masculinized rats requires elevated GABA signaling. Given that GABA is synthesized only in neurons and its synthesis is increased by estradiol, we conclude it is acting as a diffusible factor inducing the differentiation of neighboring astrocytes [55] (Fig. 3). What is unclear from our analysis is how the released GABA is directing the increase in astrocytic process length and process number.
View larger version (22K):
[in this window]
[in a new window]
|
FIG. 2. Sex differences in arcuate astrocyte morphology are mediated by GABA. A reduction in GABA levels in the arcuate of newborn males was achieved by administration of antisense oligodeoxynucleotides against the rate-limiting enzyme glutamic acid decarboxylase (GAD). When astrocyte morphology was assessed on Postnatal Day 3, males treated with GAD antisense oligos had significantly more undifferentiated (class I) astrocytes compared with males treated with control scrambled oligos. The same treatment was without effect in females, but when females were treated with the GABAA receptor agonist muscimol, there was a dramatic increase in the frequency of highly differentiated astrocytes (class IV) compared with vehicle-treated females. These data implicate GABA, a purely neuronal factor, as the mediator of hormonally directed astrocyte differentiation in the arcuate nucleus (redrawn from original data presented in [55])
|
|
View larger version (22K):
[in this window]
[in a new window]
|
FIG. 3. Schematic representation of gamma-amino butyric acid (GABA) as a messenger of differentiation from neurons to astrocytes in the developing arcuate nucleus. Estradiol increases the synthesis of neuronal GABA by upregulating the expression of its synthetic enzyme, GAD. GABA diffuses from the neuron and binds the GABAA receptors of nearby astrocytes. Activation of these receptors generates a local depolarization sufficient to activate voltage-gated calcium channels (VGCC), causing a transient influx of calcium (Ca2+). Though brief, this increase in internal Ca2+ may trigger any of several Ca2+-dependent second messenger systems, including those responsible for the polymerization of glial fibrillary acidic protein and the subsequent differentiation of the astrocyte. The increased complexity of the astrocytic processes could generate steric interference, disrupting the ability of neurons to synaptically connect to one another and subsequently reduce the formation of dendritic spines
|
|
Activation of the GABAA receptor and subsequent increase in intracellular Ca2+ concentrations may initiate a myriad of second messenger cascades, some of which lead to the activation of protein kinases and phosphatases. The polymerization of GFAP, which has been implicated in the morphologic plasticity of astrocytes, is modulated by the dephosphorylation of individual subunits [56]. Although little evidence exists on the relation between GABAA receptor activation and the phosphorylation state of GFAP, it is tempting to speculate that GABA-induced astrocyte differentiation is mediated through the deactivation of specific protein kinases and/or activation of phosphatases. These would modulate the phosphorylation state of GFAP, resulting in astrocytic process extension and branching.
We have previously demonstrated that, coincident with steroid-induced changes in astrocyte morphology in the neonatal rat arcuate, there exists a twofold reduction in the number of dendritic spines [27], and quantitative electron microscopy analysis confirms that these changes translate into sexually dimorphic synaptic patterning. At 3 days old, gonadally intact males have 54% fewer and masculinized females have 77% fewer axospinous synapses than intact females [29]. The precise cellular and molecular mechanisms of gonadal steroid-mediated changes in synaptic patterns are unknown, but numerous in vivo and in vitro studies have demonstrated a critical role for astrocytes in synapse formation and elimination (reviewed in [57]). In particular, the adult female arcuate undergoes reversible synaptic remodeling in response to hormonal fluctuations across the estrous cycle [58]. The structural plasticity of astrocytic processes is integral to this synaptic remodeling in the adult female [21, 59, 60]. The synaptic changes in the adult female arcuate neuroarchitecture are accompanied by prominent changes in the surface area covered by the astrocytes such that, when circulating estrogen is high, astrocytic surface area is increased. Electron microscopy demonstrates that these extended astrocytic processes ensheath the arcuate neurons, thereby preventing inhibitory synaptic inputs and resulting in the loss of synapses. Estradiol's effect on astrocytes is dependent on physical contact with hypothalamic neurons [61, 62]. Moreover, when the expression of the polysialic acid form of NCAM (PSA-NCAM), a neural cell adhesion molecule implicated in synaptic plasticity, is perturbed in the arcuate of adult female rats, the estradiol-induced synaptic remodeling is inhibited [63]. Based on these observations in the adult arcuate, we postulate that the extended astrocytic processes present in masculinized brains early in development are juxtaposed between neighboring neurons, resulting in a block of synaptic neurotransmission that ultimately leads to the loss of the synapse. For reasons that are not understood, the loss of synapses during this developmental time period is permanent, resulting in a lifelong sexually dimorphic brain.
In the preoptic area, astrocytes show a similar sexual dimorphism to that seen in the arcuate nucleus. Preoptic area astrocytic processes in males are longer and exhibit more complex branching patterns than those seen in females (Fig. 4). However, markers of dendritic spine density in the preoptic area reveal the opposite pattern to that seen in the arcuate, with males having more dendritic spines than females [26], a sex difference also found in the adult primate brain [64]. Thus, in this brain region, there is no simple physical relationship between astrocytes and neurons in which increased astrocytes appear to suppress the formation of dendritic spines. An alternative mechanism suggested by the literature but that remains to be tested is the potential for local release of glutamate from astrocytes that then acts on neighboring neurons to induce and/or maintain spines and their excitatory synapses. A developmental strategy in which estradiol differentially modulates specific amino acids to induce permanent changes in synaptic patterning would maximize the potential for region-specific responses achieved by a single gonadal steroid.
View larger version (96K):
[in this window]
[in a new window]
|
FIG. 4. Astrocytes of the developing male preoptic area (POA) are more complex than those of the female. A) Representative photomicrographs demonstrating the increased complexity of male astrocytes in the newborn POA. Astrocytes were visualized by immunocytochemistry for GFAP (bar = 25 µm). B) Quantification of the mean primary process length and the average number of primary processes per astrocyte in the POA was performed using the Neurolucida image analysis system. Astrocytes of the developing newborn male rat POA have both longer (ANOVA; *P < 0.01, n = 6) and a greater number of primary processes (ANOVA; *P < 0.01) compared with females
|
|
|
FUNCTIONAL SIGNIFICANCE OF STEROID-INDUCED CHANGES IN ASTROCYTE MORPHOLOGY
|
|---|
The arcuate nucleus of the hypothalamus modulates release of LH, growth hormone, and prolactin from the anterior pituitary. In the adult female rat, neurons of the arcuate nucleus show phased synaptic remodeling across the estrous cycle. These modifications are characterized by a decrease in axosomatic synapses when circulating estrogen levels are high [58]. Immunocytochemical studies indicate these axosomatic synapses are primarily GABAergic [65] and the decrease in the number of inhibitory synapses may contribute to the estrogen-induced increase in arcuate neuronal firing that is correlated with increased release of LH [66, 67]. Masculinized rat brains do not exhibit estrogen-induced release of GnRH and the subsequent LH surge. In fact, the astrocytic and synaptic remodeling of the arcuate nucleus in response to estrogen is sexually dimorphic and only seen in adult female rat brains [68]. It is likely that the early estradiol-induced differentiation of the arcuate astrocytes in males contributes to the loss of plasticity in adulthood. The ability of antisense oligodeoxynucleotides to GAD mRNA to block the masculinization of arcuate astrocytes during development provided a tool for assessing the importance of sexual differentiation of astrocytes to the adult LH surge. Toward this end, neonatal males were treated with GAD antisense oligodeoxynucleotides, scrambled control oligodeoxynucleotides, or saline and then raised to adulthood. Following gonadectomy, males were treated with a hormonal regime optimal for inducing an LH surge in females. Control males exhibited little to no LH release in response to hormonal treatment, as would be expected, but males that had been treated with GAD antisense oligodeoxynucleotides as neonates had a threefold increase in LH levels compared with controls (Fig. 5). These data support the notion that the differentiation of arcuate astrocytes early in development is important to sex differences in the control of gonadotropin secretion.
View larger version (14K):
[in this window]
[in a new window]
|
FIG. 5. Blocking differentiation of arcuate astrocytes in males allows for an LH surge. Rat pups were treated with GAD antisense oligodeoxynucleotides and control scrambled oligodeoxynucleotides in the same manner as in Figure 3 and were raised to adulthood. Following gonadectomy, animals were treated with estradiol and progesterone in a regime known to reliably induce an LH surge. Blood samples were collected by cardiac puncture at the predicted time of the LH surge and assayed for such. There was no evidence of LH release in males that had been treated as neonates with saline vehicle or scrambled oligodeoxynucleotides, but there was a significant increase in LH release in males treated with GAD antisense oligodeoxynucleotides (ANOVA; *P < 0.05 compared with saline, n = 6–8 per group). Based on the observation that treatment with GABA antisense oligodeoxynucleotides blocks the masculinization of astrocytes, we conclude that the morphology of arcuate astrocytes plays a role in control of the LH surge
|
|
The preoptic area is a brain region with a wholly different function than that of the arcuate nucleus. While the majority of GnRH neurons are located in this brain region, they are not in the medial preoptic nucleus, the primary site in which sexually dimorphic astrocytic and neuronal morphologies are found. However, this is the primary site for the control of a highly sexually dimorphic behavior, male sexual behavior, manifested as mounting, intromitting, and ejaculating into a receptive female [12]. It is also a central brain region for the control of maternal behavior [69], yet another hormonally mediated sexually dimorphic behavior. Last, the preoptic area plays a suppressive modulatory role in the control of the female sexual response characterized by the lordosis posture. By establishing the mechanisms of estradiol-mediated sexually dimorphic patterning in this brain region, functional relationships between neuronal morphology and complex behaviors can begin to be made.
|
SUMMARY AND CONCLUSIONS
|
|---|
The central importance of glia, and in particular astrocytes, to the establishment of synapses in the developing brain is an emerging concept. Parallel to this newfound appreciation for astrocytes has been a growing awareness that they are also targets of steroid hormone modulation and that this may be a fundamental mechanism by which estradiol alters neuronal morphology. Of particular interest, however, is that estradiol appears to exploit the varied potential of astrocytes in a regionally specific manner. In the arcuate nucleus, GABA serves as the conduit for cross talk between neurons and astrocytes, inducing a morphologic change in the latter that then alters the formation of spinous synapses in the former. In the preoptic area, the messenger(s) involved in the cross talk between the two cell types is not known, but the morphologic relationship between the two cell types is fundamentally different, with increased astrocyte complexity correlating positively with increased spine density (Fig. 6). In yet a third brain region, the ventromedial nucleus of the hypothalamus, there is no obvious relationship between astrocytes and any aspect of neuronal morphology. These three different scenarios illustrate how we are just scratching the surface of possible ways in which steroid modulation of astrocytes can alter brain development and ultimately reproductive functioning.
View larger version (34K):
[in this window]
[in a new window]
|
FIG. 6. The physiologic importance of sex differences in astrocyte morphology is likely to be region specific. The astrocytes of neonatal males are more complex, with longer and more frequently branching processes, than those of females in both the POA and the arcuate nucleus. However, the correlation between astrocytic and neuronal morphology is the opposite in these two brain regions, with males having more dendritic spine synapses in the POA and less in the arcuate compared with females. The POA is a major brain region controlling male sexual behavior, whereas the arcuate appears important to sexually dimorphic control of gonadotropin secretion from the pituitary. Differences in neuronal morphology, as determined by neighboring astrocytes, may underlie these sex differences in physiology and behavior
|
|
|
FOOTNOTES
|
|---|
First decision: 24 January 2002.
1 Correspondence: Margaret M. McCarthy, Department of Physiology and Program in Neuroscience, University of Maryland, 655 Baltimore St., Baltimore, MD 21201-1559. FAX: 410 706 8341; mmccarth{at}umaryland.edu 
Accepted: April 5, 2002.
Received: January 8, 2002.
|
REFERENCES
|
|---|
-
Harley V, Goodfellow P. The biochemical role of SRY in sex determination. Mol Reprod Dev 1994 39:184-193[CrossRef][Medline]
-
Gerall AA, Moltz H, Ward IL. Handbook of Behavioral Neurobiology: Sexual Differentiation. New York: Plenum Press; 1992
-
Matsumoto T, Yamanouchi K. Acceleration of mounting behaviors in female rats by ibotenic acid lesions in the ventromedial hypothalamic nucleus. Neurosci Lett 2000 291:143-146[CrossRef][Medline]
-
Weisz J, Ward IL. Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses and neonatal offspring. Endocrinology 1980 106:306-313[Abstract/Free Full Text]
-
Rochellys Diaz D, Fleming D, Rhees R. The hormone-sensitive early postnatal periods for sexual differentiation of feminine behavior and luteinizing hormone secretion in male and female rats. Dev Brain Res 1995 86:227-232[CrossRef][Medline]
-
Sagrillo CA, Grattan DR, McCarthy MM, Selmanoff M. Hormonal and neurotransmitter regulation of GnRH gene expression and related reproductive behaviors. Behav Genet 1996 26:241-277[CrossRef][Medline]
-
Smith MJ, Jennes L. Neural signals that regulate GnRH neurones directly during the oestrous cycle. Reproduction 2001 122:1-10[Abstract]
-
Han SK, Abraham IM, Herbison AE. Effect of GABA on GnRH neurons switches from depolarization to hyperpolarization at puberty in the female mouse. Endocrinology 2002 143:1459-1466[Abstract/Free Full Text]
-
Herbision AE. Estrogen regulation of GABA transmission in rat preoptic area. Brain Res Bull 1998 44:321-326
-
Garcia-Segura LM, Chowen JA, Duenas M, Torres-Aleman I, Naftolin F. Gonadal steroids as promoters of neuro-glial plasticity. Psychoneuroendocrinology 1994 19:445-453[CrossRef][Medline]
-
Pfaff DW, Schwartz-Giblin S, McCarthy MM, Kow L-M. Cellular and molecular mechanisms of female reproductive behaviors. In: Knobil E, Neill JD (eds.), Physiology of Reproduction, vol. 2, 2nd ed. New York: Raven Press; 1994: 107–220
-
Meisel RL, Sachs BD. The physiology of male sexual behavior. In: Knobil E, Neill JD (eds.), Physiology of Reproduction, vol. 2, 2nd ed. New York: Raven Press; 1994: 3–106
-
Hatten ME. Riding the glial monorail: a common mechanism for glial-guided neuronal migration in different regions of the developing mammalian brain. Trends Neurosci 1990 13:179-184[CrossRef][Medline]
-
Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR. Neurons derived from radial glial cells establish radial units in neocortex. Nature 2001 409:714-720[CrossRef][Medline]
-
Eng LF. GFAP: the major protein of glial intermediate filaments in differentiated astrocytes. J Neurosci 1985 8:203-214
-
Gooday D. Retinal axons in Xenopus laevis recognize differences between tectal and diencephalic glial cells in vitro. Cell Tissue Res 1990 259:595-598[CrossRef][Medline]
-
Le Roux PD, Reh TA. Independent regulation of primary dendritic and axonal growth by maturing astrocytes in vitro. Neurosci Lett 1995 198:5-8[CrossRef][Medline]
-
Le Roux PD, Reh TA. Regional differences in glial-derived factors that promote dendritic outgrowth from mouse cortical neurons in vitro. J Neurosci 1994 14:4639-4655[Abstract]
-
Parducz A, Perez J, Garcia-Segura LM. Estradiol induces plasticity of GABAergic synapses in the hypothalamus. Neuroscience 1993 53::395-401[CrossRef][Medline]
-
Garcia-Segura LM, Cardona-Gomez GP, Trejo JL, Fernandez-Galaz MC, Chowen JA. Glial cells are involved in organizational and activational effects of sex hormones in the brain. In: Matsumoto A (ed.), Sexual Differentiation of the Brain. Boca Raton, FL: CRC Press; 2000: 83–93
-
Garcia-Segura LM, Luquin S, Parducz A, Naftolin F. Gonadal hormone regulation of glial fibrillary acidic protein immunoreactivity and glial ultrastructure in the rat neuroendocrine hypothalamus. Glia 1994 10:59-69[CrossRef][Medline]
-
Garcia-Segura LM, Chowen JA, Naftolin F. Endocrine glia: roles of glial cells in the brain actions of steroid and thyroid hormones and in the regulation of hormone secretion. Front Neuroendocrinol 1996 17::180-211[CrossRef][Medline]
-
Garcia-Segura LM, Canas B, Parducz A, Rougon G, Theodosis D, Naftolin F, Torres-Aleman I. Estradiol promotion of changes in the morphology of astroglia growing in culture depends on the expression of polysialic acid of neural membranes. Glia 1995 13:209-216[CrossRef][Medline]
-
Mong JA, Kurzweil RL, Davis AM, Rocca MS, McCarthy MM. Evidence for sexual differentiation of glia in rat brain. Horm Behav 1996 30:553-562[CrossRef][Medline]
-
Mong JA, McCarthy MM. Steroid-induced developmental plasticity in hypothalamic astrocytes: Implications for synaptic patterning. J Neurobiol 1999 40:602-619[CrossRef][Medline]
-
Amateau SK, Mong JA, McCarthy MM. Steroid-mediated differentiation of astrocytes in the rat perinatal POA. Soc Neurosci 2000 26::224.33
-
Mong JA, Glaser E, McCarthy MM. Gonadal steroids promote glial differentiation and alter neuronal morphology in the developing hypothalamus in a regionally specific manner. J Neurosci 1999 19::1464-1472[Abstract/Free Full Text]
-
Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science 2001 291:657-661[Abstract/Free Full Text]
-
Mong JA, Roberts RC, Kelly JJ, McCarthy MM. Gonadal steroids reduce the density of axospinous synapses in the developing rat arcuate nucleus: an electron microscopy analysis. J Comp Neurol 2001 432:259-267[CrossRef][Medline]
-
Amateau SK, McCarthy MM. A novel mechanism of spine formation via estradiol induction of prostaglandin-E2. Soc Neurosci 2001 27::697.1
-
Erlander MG, Tobin AJ. The structural and functional heterogeneity of glutamic acid decarboxylase: a review. Neurochem Res 1991 16::215-226[CrossRef][Medline]
-
Esclapez M, Tillakaratne NJK, Kaufman DL, Tobin AJ, Houser CR. Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci 1994 14:1834-1855[Abstract]
-
McCarthy MM, Schwartz-Giblin S, Pfaff DW. Intracerebral administration of antisense oligodeoxynucleotides to GAD-65 and GAD-67 mRNAs modulate reproductive behavior in the female rat. Brain Res 1994 636:209-220[CrossRef][Medline]
-
McCarthy MM, Malik K, Feder HH. Increased GABAergic neurotransmission in medial hypothalamus facilitates lordosis but has the opposite effect in preoptic area. Brain Res 1990 507:40-44[CrossRef][Medline]
-
Agmo A, Paredes R. GABAergic drugs and sexual behavior in the male rat. Eur J Pharmacol 1985 112:371-378[CrossRef][Medline]
-
Léránth C, Sakamoto H, Maclusky NJ, Shanabrough M, Naftolin F. Estrogen responsive cells in the arcuate nucleus of the rat contain glutamic acid decarboxylase (GAD): an electron microscope immunocytochemical study. Brain Res 1985 331:376-381[CrossRef][Medline]
-
Leranth C, Roth RH, Elswoth JD, Naftolin F, Horvath TL, Redmond DE Jr. Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson's disease and memory. J Neurosci 2000 20:8604-8609[Abstract/Free Full Text]
-
Lamberts R, Vijayan E, Graf M, Mansky T, Wuttke W. Involvement of preoptic-anterior hypothalamic GABA neurons in the regulation of pituitary LH and prolactin release. Exp Brain Res 1983 52:356-362[Medline]
-
McCarthy MM, Kaufman LC, Brooks PJ, Pfaff DW, Schwartz-Giblin S. Estrogen modulation of mRNA levels for the two forms of glutamic acid decarboxylase (GAD) in the female rat brain. J Comp Neurol 1995 360:685-697[CrossRef][Medline]
-
Grattan DR, Rocca MS, Strauss KI, Sagrillo CA, Selmanoff M, McCarthy MM. GABAergic neuronal activity and mRNA levels for both forms of glutamic acid decarboxylase (GAD65 and GAD67) are reduced in the diagonal band of Broca during the afternoon of proestrous. Brain Res 1996 733:46-55[CrossRef][Medline]
-
Davis AM, Ward SC, Selmanoff M, Herbison AE, McCarthy MM. Developmental sex differences in amino acid neurotransmitter levels in hypothalamic and limbic areas of rat brain. Neuroscience 1999 90::1471-1482[CrossRef][Medline]
-
Davis AM, Grattan DR, Selmanoff MK, McCarthy MM. Sex differences in glutamic acid decarboxylase mRNA in neonatal rat brain: implications for sexual differentiation. Horm Behav 1996 30:538-552[CrossRef][Medline]
-
Auger AP, Perrot-Sinal TS, McCarthy MM. Excitatory versus inhibitory GABA as a divergence point in steroid-mediated sexual differentiation of the brain. Proc Natl Acad Sci U S A 2001 98:8059-8064[Abstract/Free Full Text]
-
Poulter MO, Brown LA. Transient expression of GABAA receptor subunit mRNAs in the cellular processes of cultured cortical neurons and glia. Mol Brain Res 1999 69:44-52[Medline]
-
Fraser DD, Duffy S, Angelides KJ, Perez-Velazquez JL, Kettenmann H, MacVicar BA. GABAA/benzodiazepine receptors in acutely isolated hippocampal astrocytes. J Neurosci 1995 15:2720-2732[Abstract]
-
Fraser CL, Swanson RA. Female sex hormones inhibit volume regulation in rat brain astrocyte culture. Am J Physiol 1994 267:C909-C914[Abstract/Free Full Text]
-
Barres BA, Chun LLY, Corey DP. Ion channels in vertebrate glia. Annu Rev Neurosci 1990 13:441-474[CrossRef][Medline]
-
Levitan ES, Schofield PR, Burt DR, Rhee LM, Wisden W, Kohler M, Fujita N, Rodrigues HF, Stephenson A, Darlison MG, Barnard EA, Seeburg PH. Structural and functional basis for GABA-A receptor heterogeneity. Nature 1988 335:76-79[CrossRef][Medline]
-
Burt DR. GABA-A receptor activated chloride channels. In: Guggino W (ed.), Current Topics in Membranes, vol. 42. New York: Academic Press; 1994: 215–263.
-
Kang J, Jiang L, Goldman SA, Nedergaard M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat Neurosci 1998 1:683-692[CrossRef][Medline]
-
Matsutani S, Yamamoto N. Neuronal regulation of astrocyte morphology in vitro is mediated by GABAergic signaling. Glia 1997 20::1-9[CrossRef][Medline]
-
Davis AM, Grattan DR, Selmanoff M, McCarthy MM. Sex differences in glutamic acid decarboxylase mRNA in neonatal rat brain: implications for sexual differentiation. Horm Behav 1996 30:538-552
-
Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-alpha and beta mRNA in the rat central nervous system. J Comp Neurol 1997 388:507-525[CrossRef][Medline]
-
Leranth C, Sakamoto H, Maclusky NJ, Shanabrough M, Naftolin F. Estrogen responsive cells in the arcuate nucleus of the rat contain glutamic acid decarboxylase (GAD): an electron microscopic immunocytochemical study. Brain Res 1985 331:376-381
-
Mong JA, Nunez JL, McCarthy MM. GABA mediates steroid-induced astrocyte differentiation in the neonatal rat hypothalamus. J Neuroendocrinol 2002 14:1-16[CrossRef][Medline]
-
Gottfried C, Valentim L, Salbego C, Karl J, Wofchuk ST, Rodnight R. Regulation of protein phosphorylation in astrocyte cultures by external calcium ions: specific effects on the phosphorylation of glial fibrillary acidic protein (GFAP), vimentin and heat shock protein 27 (HSP27). Brain Res 1999 833:142-149[CrossRef][Medline]
-
Laming PR, Kimelberg H, Robinson S, Salm A, Hawrylak N, Müller C, Roots B, Ng K. Neuronal-glial interactions and behavior. Neurosci Biobehav Rev 2000 24:295-340[CrossRef][Medline]
-
Olmos G, Naftolin F, Peres J, Tranque PA, Garcia-Segura LM. Synaptic remodeling in the rat arcuate nucleus during the estrous cycle. Neuroscience 1989 32:663-667[CrossRef][Medline]
-
García-Segura LM, Dueñas M, Busiguina S, Naftolin F, Chowen JA. Gonadal hormone regulation of neuronal-glial interactions in the developing neuroendocrine hypothalamus. J Steroid Biochem Mol Biol 1995 53:293-298[CrossRef][Medline]
-
García-Segura LM, Chowen JA, Parducz A, Naftolin F. Gonadal hormones as promoters of structural synaptic plasticity: cellular mechanisms. Prog Neurobiol 1994 44:279-307[CrossRef][Medline]
-
Torres-Aleman I, Rejas MT, Pons S, Garcia-Segura LM. Estradiol promotes cell shape changes and glial fibrillary acidic protein redistribution in hypothalamic astrocytes in vitro: a neuronal-mediated effect. Glia 1992 6:180-187[CrossRef][Medline]
-
García-Segura LM, Cañas B, Parducz A, Rougon G, Theodosis D, Naftolin F, Torres-Aleman I. Estradiol promotion of changes in the morphology of astroglia growing in culture depends on the expression of polysialic acid of neural membranes. Glia 1995 13:209-216
-
Hoyk Z, Parducz A, Theodosis DT. The highly sialylated isoform of the neural cell adhesion molecule is required for estradiol-induced morphological synaptic plasticity in the adult arcuate nucleus. Eur J Neurosci 2001 13:649-656[CrossRef][Medline]
-
Ayoub DM, Greenough WT, Juraska JM. Sex differences in dendritic structure in the preoptic area of the juvenile macaque monkey brain. Science 1983 219:197-198[Abstract/Free Full Text]
-
Perez J, Luquin S, Naftolin F, Garcia-Segura LM. The role of estradiol and progesterone in phased synaptic remodeling of the rat arcuate nucleus. Brain Res 1993 608:38-44[CrossRef][Medline]
-
Yeoman RR, Jenkins AJ. Arcuate area of the female rat maintained in vitro exhibits increased afternoon electrical activity. Neuroendocrinology 1989 49:144-149[Medline]
-
Kis Z, Horvath S, Hoyk Z, Toldi J, Parducz A. Estrogen effects on arcuate neurons in rat. An in situ electrophysiological study. Neuroreport 1999 10:3649-3652[Medline]
-
Horvath TL, Garcia-Segura LM, Naftolin F. Lack of gonadotrophin-positive feedback in the male rat is associated with lack of estrogen-induced synaptic plasticity in the arcuate nucleus. Neuroendocrinology 1997 65:136-140[Medline]
-
Numan M. Maternal behavior. In: Knobil E, Neill JD (eds.), Physiology of Reproduction, vol. 2. New York: Raven Press; 1994: 108–302
This article has been cited by other articles:
|
|
|
|
 
J. Kuo, O. R. Hariri, G. Bondar, J. Ogi, and P. Micevych
Membrane Estrogen Receptor-{alpha} Interacts with Metabotropic Glutamate Receptor Type 1a to Mobilize Intracellular Calcium in Hypothalamic Astrocytes
Endocrinology,
March 1, 2009;
150(3):
1369 - 1376.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Csakvari, A. Kurunczi, Z. Hoyk, A. Gyenes, F. Naftolin, and A. Parducz
Estradiol-Induced Synaptic Remodeling of Tyrosine Hydroxylase Immunopositive Neurons in the Rat Arcuate Nucleus
Endocrinology,
August 1, 2008;
149(8):
4137 - 4141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C A Wilson and D C Davies
The control of sexual differentiation of the reproductive system and brain
Reproduction,
February 1, 2007;
133(2):
331 - 359.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Gerhold and P. M. Wise
Vasoactive Intestinal Polypeptide Regulates Dynamic Changes in Astrocyte Morphometry: Impact on Gonadotropin-Releasing Hormone Neurons
Endocrinology,
May 1, 2006;
147(5):
2197 - 2202.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. V. Chaban, A. J. Lakhter, and P. Micevych
A Membrane Estrogen Receptor Mediates Intracellular Calcium Release in Astrocytes
Endocrinology,
August 1, 2004;
145(8):
3788 - 3795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Garcia-Segura and M. M. McCarthy
Minireview: Role of Glia in Neuroendocrine Function
Endocrinology,
March 1, 2004;
145(3):
1082 - 1086.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
