A Novel Mechanism of Dendritic Spine Plasticity Involving Estradiol Induction of Prostaglandin-E₂

Abstract

The mechanisms establishing and maintaining dendritic spines in the mammalian CNS remain primarily unknown. We report a novel mechanism of neuronal spine plasticity in the developing preoptic area in which estradiol induces prostaglandin-E2 (PGE2) synthesis that in turn increases the density of spine-like processes. Estradiol requires PGE2 synthesis, in vivo and in vitro, and upregulates the dendritic spine protein spinophilin, an effect attenuated by antagonism of the AMPA-kainate receptor. This signaling pathway may involve cross talk between neighboring neurons and astrocytes and appears specific to the preoptic area in that hippocampal neurons responded with an increase in spinophilin to estradiol but not PGE2. Regionally specific mechanisms of estradiol-mediated synaptic plasticity allow for epigenetic control of complex sex-typic behaviors.

Cellular mechanisms of estradiol-mediated masculinization of the brain

“…More importantly, administrating PGE2 to newborn females induces a two to three fold increase in dendritic spines (i.e. the male pattern) in the MPN, and results in the expression of masculine sexual behavior in adulthood [33,36]. Thus, PGE2 satisfies the criteria of being both necessary and sufficient to mediate steroid hormone induced masculinization of sexual behavior in the rat.…”

“…Specifically, testosterone exposure decreases the dendritic spine density and axodendritic spine synapses in the arcuate nucleus [27,31,32]. In the preoptic area (POA), a region necessary for male sex behavior, estradiol has the opposite effect and increases dendritic spine density [33]. In the VMN, a region necessary for female sex behavior, estradiol has no effect on dendritic spine density [27] but does increase the number of dendritic spines per neurite (Todd et al, 2006).…”

“…The answer appears to be at least in part via glutamate, since pretreatment with an AMPA receptor antagonist will reduce the level of spine induction bỹ 50% [33], and in other brain regions PGE2 releases glutamate from astrocytes [40,41]. These observations have led to the working hypothesis that estradiol up regulates COX-2 in neurons, increasing PGE2 production and release which then acts on neighboring astrocytes to induce glutamate release, and this then communicates back to the neurons inducing the formation of dendritic spines [42].…”

Recovery of hippocampal cell proliferation and BDNF levels, both of which are reduced by repeated restraint stress, is accelerated by chronic venlafaxine

“…Images were collected with the ImageMaster VDS (Amersham Pharmacia Biotech, Piscataway, NJ, USA), and analyzed using Image-Pro Plus (Media Cybernetics, Silver Spring, MD, USA). The results were expressed as the product of the optical density and the surface area of a given band as described by Amateau et al 56 …”

Histone modifications proposed to regulate sexual differentiation of brain and behavior

“…The sex differences found in dimorphic brain structures are not uniform in nature: some result from disproportion in cell numbers and some arise from the differences in synaptic connections or neuropil density; dimorphisms in chemical characteristics of cells and arborization have also been described [52, [69][70][71][72][73]. Moreover, most dimorphic nuclei described in rodent species are larger in males with the exception of anteroventral periventricular nucleus (AVPV), which is larger in females [70].…”