Sex-Dependent Effects of Estrogen on LTP
Weisheng Wang, Aliza A. Le, Bowen Hou, Julie C. Lauterborn, Conor D. Cox, et al.
(see pages 7935–7951)
Men and women excel at different hippocampus-dependent tasks: whereas men tend to be better at spatial navigation, women typically exhibit superior episodic memory. These sex differences are thought to stem from the effects of estrogens on hippocampal circuits. In females, cyclic variation in estrogen levels produces corresponding fluctuations in hippocampal dendritic spine density, long-term potentiation (LTP), and spatial memory performance. But even locally synthesized estrogen has different effects on male and female hippocampus, despite being present and promoting LTP in both. For example, blocking local estrogen synthesis disrupts LTP in female, but not male rodents.
To elucidate the sex-dependent effects of estrogen on LTP, Wang et al. examined changes evoked by theta-burst stimulation (TBS) of inputs to CA1 pyramidal neurons in brain slices. The molecular basis of LTP appeared nearly identical in males and females, but the engagement of these mechanisms was enhanced by activation of estrogen receptor ERα only in females. Blocking ERα did not affect TBS-evoked NMDA-receptor-dependent neuronal depolarization in females, but it impaired subsequent signaling steps, including activation of synaptic Src, ERK, and focal adhesion kinases and activation of the brain-derived neurotrophin receptor TrkB.
Although TBS trains could induce similar levels of LTP in males and females in the absence of ERα antagonists, the thresholds for synaptic activation of ERK and LTP induction and were greater in females. Both thresholds were lowered when females were treated with estradiol. Notably, estradiol also enhanced ERK activation in males, but unlike in females, ERα was not involved; moreover, synaptic levels of ERα were significantly lower in males than in females. Instead, the effect of estradiol in males was mediated by ERβ. Finally, whereas males and proestrus females (which have high levels of circulating estrogen) performed similarly with equivalent training on an object-location memory task, females outside proestrus required additional training.
These results suggest that stronger synaptic activity is required to induce LTP in female rodents than in males, but this necessity can be overcome by activation of ERα by locally produced or systemic estrogens. Future work should explore why this is the case, what the advantages might be for females, and whether similar effects occur at other synapses.
Contributions of Mast Cells to Sex Differences in the Brain
Kathryn M. Lenz, Lindsay A. Pickett, Christopher L. Wright, Katherine T. Davis, Aarohi Joshi, et al.
(see pages 8044–8059)
The best understood sex differences in the brain are found in regions that control reproductive behaviors. These regions become sexually dimorphic during fetal and early postnatal development, thus setting the stage for reproductive hormones to drive sex-specific behaviors in adulthood. In perinatal male rodents, 17β-estradiol derived from testicular testosterone promotes survival and dendritic spine formation in a nucleus of the preoptic area (POA) that drives male copulatory behaviors. Injecting newborn females with estradiol masculinizes the POA, and when these females reach adulthood, treating them with testosterone elicits male-like sexual behaviors.
Activated microglia are more abundant in male (top) than female (bottom) POA. The number is increased in females by stimulating histamine release from mast cells. See Lenz, Pickett et al. for details.
The effects of estradiol on POA spine density are mediated by prostaglandin E2 (PGE2). This signaling molecule is secreted by microglia, which are more numerous in male than in female POA. New work indicates that estradiol does not activate microglia directly, however. Instead, estradiol acts on POA mast cells, inducing them to release histamine, which then stimulates PGE2 release from microglia.
Peripheral mast cells have a prominent role in allergic responses, but their roles in the brain are poorly understood. Lenz, Pickett et al. found that mast cells are more abundant and degranulated (that is, actively secreting signaling molecules) in the POA of male rodents than in females. Moreover, mast cells expressed estrogen receptors, and injecting newborn females with estradiol increased both the number and degranulation of POA mast cells. Treating isolated mast cells with estradiol increased secretion of histamine, and medium from mast-cell cultures increased PGE2 levels and dendritic spine density in POA cultures. This occurred only if microglia were present in POA cultures, however, and histamine receptor antagonists blocked the effects. Finally, inducing mast cell degranulation in the POA of newborn female rodents increased histamine levels and activated microglia, and when these female mice reached adulthood, they exhibited male-like sexual behaviors. In contrast, inhibiting mast cell degranulation in newborn males reduced microglia activation and blunted subsequent sexual behavior.
These results indicate that mast cells are an important contributor to masculinization of the POA. Future work should investigate whether mast cells contribute to development of other brain areas. As components of the immune system, mast cells are likely activated during maternal infection, and therefore might contribute to neurodevelopmental disorders such as schizophrenia, for which maternal infection increases risk.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.