Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system.

Alessandro Tozzi,Carmela Giampã,Michela Di Mauro,Paolo Calabresi,Michela Tantucci,Valentina Durante,Petra Mazzocchetti,Cinzia Costa,Silvarosa Grassi,Ana Quiroga-Varela,Massimiliano Di Filippo,Vito Enrico Pettorossi,Antonio De Iure

doi:10.3389/fncel.2015.00192

Abstract

17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson’s disease.

Highlights

Estrogens, in particular 17β-estradiol (E2), play a fundamental role in regulating brain activity modulating neuronal expression of enzymes, receptors, structural proteins and synaptic plasticity and notably influencing cognition and behavior (Wong and Moss, 1992; Murphy and Segal, 1996; McEwen, 2002; Kramár et al, 2013)
Since we found that D1-like receptor (D1R) activation restores long-term potentiation (LTP) in the absence of endogenous E2, but does not restore it in the presence of E2 receptors (ERs) blockade, we explored whether the D1R- and ERdependent medium spiny neurons (MSNs) LTP could be mediated by extracellular signal-regulated kinase (ERK) activation
In the present study we demonstrate for the first time to our knowledge that the locally synthesized E2 is crucial for the induction of the LTP in the striatum by interacting with the downstream enzymatic cascade activated by DA

Summary

Introduction

In particular 17β-estradiol (E2), play a fundamental role in regulating brain activity modulating neuronal expression of enzymes, receptors, structural proteins and synaptic plasticity and notably influencing cognition and behavior (Wong and Moss, 1992; Murphy and Segal, 1996; McEwen, 2002; Kramár et al, 2013). It is unknown whether DA interacts with the circulating E2 or with the E2 that can be locally synthesized in the nervous system from testosterone through P450-aromatase (ARO) (Naftolin et al, 1975; Simpson et al, 1994; Balthazart et al, 2001; Kimoto et al, 2001; Hojo et al, 2004, 2008; Balthazart and Ball, 2006; Mukai et al, 2006) It has been shown a decisive role of endogenous E2 in inducing long-term potentiation (LTP) in the vestibular nuclei by acute effects (Grassi et al, 2009, 2010; Scarduzio et al, 2013) and in the hippocampus by both acute (Grassi et al, 2011; Tanaka and Sokabe, 2012; Pettorossi et al, 2013) and chronic influences (Vierk et al, 2012, 2014). In the present study we investigated the involvement of endogenous E2 in the expression of striatal synaptic plasticity and its interaction with DA demonstrating a critical cross-talk between E2 and D1-like DA-dependent signaling

Methods

Results

Conclusion