Sex Steroids and Synaptic Plasticity in Aging
Caleb E. Finch, Ph.D. Director

Irina Rozovsky, Ph.D. Co-director

 

Rozovsky I., Wei M., Stone D.J., Zanjani H., Anderson C.P., Morgan T.E., and Finch C.E., Estradiol (E2) Enhances Neurite Outgrowth by Repressing Glial Fibrilary Acidic Protein Expression and Reorganizing Laminin. Endocrinology 143(2):636-646

 

This project addresses steroidal influences on synaptic remodeling in the rodent brain in vivo and in vitro with cell culture models, with a focus on astrocyte genes that are regulated by estradiol and corticosterone.

 Specific Studies

1.     Transcriptional regulation of GFAP in astrocytes and of genes expressed in neurons that show modulation by estradiol using in vitro cell models for response to estradiol, corticosterone and injury.

2.     Effects of estradiol on synaptic plasticity in hippocampus with markers for synaptic remodeling in astrocytes and neurons using in vivo gene expression.

3.     Effects of aging on interactions of estradiol and synaptic plasticity in vivo.

 

Main findings:

 

1.  In the entorhinal cortex lesion (ECL) model of hippocampal deafferentation during 

Alzheimer, we showed in female mice that estradiol (E2) enhanced synaptophysin as

a marker for neuron sprouting (Stone et al Endocrinology 1998).  Moreover, this effect of E2 was attenuated in apoE-deficient mice (Stone et al J Neurosci 1998), consistent with prior studies showing that E2 induced apoE mRNA and secretions by astrocytes (Stone et al.  Exp Neurol  1997).  These results directly show the importance of apoE in E2-sensitive sprouting and are consistent with the impairments of synaptic plasticity in apoE deficient mice, more generally.

2.  E2 and apoE: Bioactivities of Premarin components Equilin induces apoE mRNA and secretion in cultured glia at the same sensitivity as E2 (Rozovsky et al, in prep).  This finding is consistent with positive effects of equilin on neuron outgrowth in culture by Brinton et al.  Exp Neurol 1997].

3.  Two new responses to E2: mRNAs for the presynaptic proteins synaptotagmin I and synaptophysin, which also vary during the estrous cycle  (Crispino et al., Exp Neurol 1999); collaboration with Project 4.

4.  Effects of estrogens on the GFAP gene which influences the environment of neurons by changing the shape of astrocytes that surround the synapses of neurons.

a.  The regulation of GFAP by estradiol depends on an estrogen response element (ERE) in the near upstream promoter, as shown by site directed mutagenesis  and by the binding of estrogen receptor alpha to this ERE (Stone et al., Endocrinology 1998).

b.  As a model for complex cell interactions of E2 in vivo, we developed the wounding in a dish model in which neurons are grown over a layer of astrocytes. Astrocytes showed robust induction of GFAP transcription by wounding that was blocked by E2.  GFAP promoter regions were identified that mediate responses to wounding and interactions with E2 (Rozovsky et al., submitted). E2 also enhanced neuronal sprouting and extracellular laminin reorganization.  Previously, Lefrancoise et al (J Neuroscience 1997) shown in this same model that down regulation of GFAP mRNA and protein by antisense GFAP had exactly the same effect as E2 on sprouting and laminin.  Thus, in two examples,  inhibition of GFAP is sufficient for enhancing sprouting by reorganization of laminin. This is the first indication that brain laminin is controlled by sex steroids.   We hypothesize that E2 regulates a cascade of astrocyte cytoskeletal proteins through GFAP transcription, with downstream effects on laminin and, in turn, on neurite outgrowth.


 __________________________________________________

 

Caleb E. Finch, Ph.D. (PI)
cfinch@molbio.usc.edu

Irina Rozovsky, Ph.D.
rozovsky@molbio.usc.edu

Christopher P. Anderson, Ph.D.
cpanders@molbio.usc.edu

Todd Morgan
temorgan@usc.edu

 

Publications

 

  1. Stone DJ, Rozovsky I, Morgan TE, Anderson CP, Lopez LM, Shick J, Finch CE.  Effect of age on gene expression during estrogen-induced synaptic sprouting in female rat. Exp Neurol 165:46-57, 2000.  (PDF file)

 

  1. Li R, Shen Y, Yang LB, Lue LF, Finch C, RogersJ (2000)  Estrogen enchances uptake of amyloid beta-protein by microglia derived from the human cortex.  J Neurochem. 75:1447-1454   (PDF file)

 

  1. Anerson CP, Rovzovsky I, Stone DJ, Song Y, Lopez LM, and Finch CE.  Reproductive aging and the regulation of GFAP in hypothalamic astrocytes in the female rat: dissociations of GFAP induction from the induced LH-surge, submitted.

 

  1. Rozovsky I, Wei M, Stone DJ, Zhanzani H, Song Y, Anderson CP, Morgan TW, Lopez LM, and Finch CE.  Estrogen suppresses GFAP induction during astrocyte responses to injury and enhances neurite outgrowth, submitted.

 

  1. deBruin JP, Gosden RG, Finch CE Leaman BN, Oocytes, follicles, and aging in two species of long-lived rockfish, Sebastes aleutianus and S. Alutus, Submitted

 

 Estrogen Main | Project 2  | Project 3  | Project 4  | Project 5  | Publications