The Journal of Steroid Biochemistry and Molecular Biology
Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen☆
Introduction
Occurrence of local synthesis of estrogen and androgen in the adult hippocampus supports estrogen-dependent regulation of memory processes which occur rapidly [1], [2], [3], [4], [5]. Different from circadian rhythm-dependent synthesis that occurs in ovary or testis, synaptic synthesis (transient and rapid) of estrogen and androgen could occur dependent on synaptic events including long-term potentiation (LTP) and long-term depression (LTD) [1], [2], [3], [4], [5].
Not only electrophysiological properties but also dendritic spines have been studied in relation to memory processes and synaptic plasticity which are regulated by neurotransmitters, because synapse is a site of memory storage and spine is a postsynaptic structure.
For decades, neuromodulatory actions of gonadal sex hormones have been extensively investigated, because circulating sex hormones can penetrate into the hippocampus by crossing the blood–brain barrier. Genomic slow modulation of synaptogenesis or electrophysiological properties is investigated by estrogen replacement for ovariectomized female rats [6], [7], [8], [9], [10], [11]. An increase of synapses or an enhancement of synaptic transmission is observed upon estrogen replacement of ovariectomized animals. Genomic slow modulation of spines is also observed in slice cultures [6], [7], [8], [9], [10], [11]. These slow genomic effects are mediated via nuclear estrogen receptors ERα/ERβ which initiate transcription processes. The slow/genomical modulation of NR2B by 17β-estradiol (E2) replacement enhances LTP in ovariectomized rat [12], [13].
The acute/rapid effect of E2 (within 1–2 h) also occurs by modulating spine density or synaptic transmission of the hippocampal slices [6], [7], [14], [15], [16], [17]. Acute modulation of synapses by E2 occurs via synaptic ERα/ERβ which drives kinases in their downstream [16], [18]. Since kinases not only work within synapses but also move into nuclei to drive gene transcription, acute E2 effects also drive genomic processes which may slowly enhance synaptic contacts.
These acute modulations, relating to memory formation processes, favor locally synthesized steroids rather than circulating gonadal hormones which travel a long distance before reaching the brain. Rather than being a limiting factor, a weak activity of sex steroid production in the hippocampus is sufficient for the local usage within small volume of neurons (i.e., an intracrine system). This intracrine system contrasts with the endocrine organs in which high expression levels of steroidogenic enzymes are necessary to supply steroids to many other organs via the blood circulation. For hippocampus-derived sex hormones, one of the essential functions may be the rapid and repetitive modulation of synaptic plasticity and cognitive functions, in addition to genomic slow modulation.
Section snippets
Modulation of long-term potentiation (LTP) and long-term depression (LTD)
Nanomolar level of E2 exerts an acute influence (0.5–1 h) on the synaptic transmission of hippocampal slices, as demonstrated by electrophysiological investigations.
Interestingly, the effects of E2 on the basal excitatory postsynaptic potential (EPSP) or LTP may strongly depend on the age of rats. In the hippocampus from 4- to 6-week-old or 200 to 350 g (approx. 6–8 week-old) Sprague-Dawley rats, perfusion of 1–10 nM E2 rapidly increases the basal EPSP (thereby enhances LTP) at CA3–CA1 synapses [6]
Pathway of synthesis (Fig. 7)
Sex steroids had been thought to reach the brain exclusively via blood circulation after crossing the blood–brain barrier [72]. However, recent studies using immunohistochemical staining and Western immunoblot analysis reveal a significant localization of steroidogenic proteins such as cytochromes P450scc, P450 (17α), P450arom and StAR in pyramidal neurons in CA1–CA3, as well as in granule cells in DG, of adult hippocampus (12 week) (Fig. 7) [1], [2], [3], [4], [18], [73], and also
Difference between classical slow genomic modulation and rapid synaptic modulation by estrogen
Not only slow (gene transcriptional) but also rapid (kinase driving) estrogen signaling occurs independently in the brain (Fig. 10).
Model explanation of modulation of synaptic plasticity by sex steroids in relation to synaptocrine and intracrine mechanisms (Fig. 10)
Rapid modulation is triggered by E2 binding to synaptic ERα, resulting in activation of many kinases (MAPK, PKA, PKC, PI3K or even phosphatases), followed by modulation of NMDA receptors (NMDA type glutamatergic receptors) or AMPA receptors (AMPA type glutamatergic receptors). E2-induced phosphorylation of NR2B subunit by MAPK activation occurs [24]. E2-induced phosphorylation of AMPA receptors by these kinases is not well examined. For spine formation, MAPK induced phosphorylation of cortactin
References (108)
- et al.
Methods Enzymol.
(2002) - et al.
Adv. Biophys.
(2003) - et al.
Biochim. Biophys. Acta
(2003) Horm. Behav.
(1998)- et al.
Neuroscience
(2006) - et al.
Biochem. Biophys. Res. Commun.
(2005) - et al.
Mol. Cell. Endocrinol.
(2008) - et al.
Brain Res. Rev.
(2008) - et al.
Brain Res. Bull.
(2000) - et al.
Neuron
(1998)
Brain Res.
Biochim. Biophys. Acta
Biochem. Biophys. Res. Commun.
Biochem. Biophys. Res. Commun.
Mol. Cell. Endocrinol.
Neuroscience
Brain Res.
Neuroscience
Biochem. Biophys. Res. Commun.
Steroids
Biochem. Biophys. Res. Commun.
Brain Res.
Epilepsy Res.
J. Lipid Res.
J. Chromatogr. B: Biomed. Sci. Appl.
Steroids
Brain Res. Brain Res. Rev.
Endocrinology
Proc. Natl. Acad. Sci. U.S.A.
J. Neurosci.
Proc. Natl. Acad. Sci. U.S.A.
J. Neurophysiol.
J. Neurophysiol.
J. Neurosci.
J. Neurosci.
Hippocampus
Science
J. Neurochem.
J. Neurosci.
Environ. Sci.
J. Physiol.
Cereb. Cortex
PLoS ONE
Nature
Proc. Natl. Acad. Sci. U.S.A.
J. Neurophysiol.
Neuroendocrinology
J. Neurosci.
Neuroscientist
Cereb. Cortex
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This article is part of a Special Issue entitled ‘Neurosteroids’.