Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion.

Veronica Ghiglieri,Daniela Vitucci,Valentina Pendolino,Barbara Pelosi,Francesco Napolitano,Sara Migliarini,Carmela Giampà,Robert Nisticò,Giuseppe Sciamanna,Barbara Picconi,Alessandro Usiello,Giacomo Maddaloni,Massimo Pasqualetti,Anna Di Maio,Francesco Errico,Maria Mancini,Chiara Schepisi

doi:10.1038/srep10933

Abstract

Mechanisms of gender-specific synaptic plasticity in the striatum, a brain region that controls motor, cognitive and psychiatric functions, remain unclear. Here we report that Rhes, a GTPase enriched in medium spiny neurons (MSNs) of striatum, alters the striatal cAMP/PKA signaling cascade in a gender-specific manner. While Rhes knockout (KO) male mice, compared to wild-type (WT) mice, had a significant basal increase of cAMP/PKA signaling pathway, the Rhes KO females exhibited a much stronger response of this pathway, selectively under the conditions of dopamine/adenosine-related drug challenge. Corticostriatal LTP defects are exclusively found in A2AR/D2R-expressing MSNs of KO females, compared to KO males, an effect that is abolished by PKA inhibitors but not by the removal of circulating estrogens. This suggests that the synaptic alterations found in KO females could be triggered by an aberrant A2AR/cAMP/PKA activity, but not due to estrogen-mediated effect. Consistent with increased cAMP signaling, D1R-mediated motor stimulation, haloperidol-induced catalepsy and caffeine-evoked hyper-activity are robustly enhanced in Rhes KO females compared to mutant males. Thus Rhes, a thyroid hormone-target gene, plays a relevant role in gender-specific synaptic and behavioral responses.

Highlights

The Ras homolog enriched in striatum (Rhes) is a small GTP-binding protein discovered by subtractive hybridization[1] and highly expressed throughout the dorsal striatum and nucleus accumbens of rodent brain[2,3,4]
As a marker of GABAergic medium spiny neurons (MSNs) we used protein phosphatase 1 regulatory subunit 1B (PPP1R1B), known as Darpp[32], a bifunctional signal transduction molecule, whose phosphorylation and function is regulated by dopaminergic and adenosine receptor stimulation[26]
We found that the MSNs that did not respond to high frequency stimulation (HFS) with a physiological magnitude of long-term potentiation (LTP) in KO females were adenosine A2AR-positive cells that belong to the D2R-expressing striato-pallidal pathway (Fig. 4D–F)

Summary

Introduction

The Ras homolog enriched in striatum (Rhes) is a small GTP-binding protein discovered by subtractive hybridization[1] and highly expressed throughout the dorsal striatum and nucleus accumbens of rodent brain[2,3,4]. In addition to its influence on cAMP accumulation, Rhes acts as a selective striatal E3-ligase of mutant huntingtin, the sumoylation of which promotes neurotoxicity[11,12,13] These in vitro observations together with in vivo findings[14] are consistent with the hypothesis that Rhes-mediated functions are common striatal targets for selective neurodegeneration in basal ganglia disorders[15]. It has been found that Rhes mediates AKT-mediated signaling[16,17], participates in intracellular iron homeostasis[18] and, most notably, modulates mammalian target of rapamycin complex 1 (mTORC1) This critical pathway is associated, among other processes[19], with L-DOPA-induced dyskinesia (LID) in animal models of Parkinson disease[20,21]. Our study indicates that Rhes orchestrates gender-sensitive alterations in striatal signaling, synaptic plasticity, and behavioral responses

Methods

Results

Conclusion