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

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.

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors’ in Mice

“…Here, we first confirmed a consistent Rasd2 mRNA expression in the mouse striatum (Errico et al, 2008;Ghiglieri et al, 2015;Vargiu et al, 2001) ( Figure 1a), and extended our study of Rasd2 gene expression pattern to the human brain, where we reported a highly enriched RASD2 mRNA expression in the putamen but not in the surrounding brain regions, such as globus pallidus and claustrum (Figure 1e-g). Moreover, consistent with previous findings in rodents (Vargiu et al, 2001), we found scattered Rasd2 mRNA-positive neurons distributed throughout the cortical layers, with an autoradiographic signal that appeared higher in layers (L) II-III than in deeper ones (Figure 1a and b).…”

“…Rasd2 negatively modulates G protein-coupled receptor-mediated cAMP production (Vargiu et al, 2004). Consistently, targeted deletion of this gene in mice results in increased striatal cAMP/PKA signaling (Errico et al, 2008;Ghiglieri et al, 2015). Besides its well-established expression within striatal GABAergic medium spiny-projecting neurons, we recently demonstrated that Rasd2 is also virtually localized in all cholinergic interneurons in humans and mice, where it affects DA D2R-dependent firing activity and signaling (Sciamanna et al, 2015).…”

“…Importantly, this transcriptional regulation is most likely mediated by thyroid receptor α (TRα) as, differently from what observed in TRα knockout mice, T3 supplementation induces an upregulation of Rasd2 mRNA in hypothyroid TRβ mutants (Vallortigara et al, 2008). Rasd2 encodes for a small GTP-binding protein highly expressed in the striatum and nucleus accumbens of rodents (Errico et al, 2008;Vargiu et al, 2004), where it affects neuronal processes associated with cAMP/PKA and AKT signaling transduction cascades (Ghiglieri et al, 2015;Harrison and Lahoste, 2013). Furthermore, Rasd2 also influences DA D1R-and D2R-related processes within striatal GABAergic projection neurons and cholinergic interneurons (Errico et al, 2008;Ghiglieri et al, 2015;Sciamanna et al, 2015).…”

“…Rasd2 encodes for a small GTP-binding protein highly expressed in the striatum and nucleus accumbens of rodents (Errico et al, 2008;Vargiu et al, 2004), where it affects neuronal processes associated with cAMP/PKA and AKT signaling transduction cascades (Ghiglieri et al, 2015;Harrison and Lahoste, 2013). Furthermore, Rasd2 also influences DA D1R-and D2R-related processes within striatal GABAergic projection neurons and cholinergic interneurons (Errico et al, 2008;Ghiglieri et al, 2015;Sciamanna et al, 2015). On the other hand, recent studies have suggested that Rasd2, through SUMO and mTOR pathway regulation, has a pivotal role in the genesis of neurological disorders involving the striatum, such as Huntington's disease (Lee et al, 2015;Subramaniam et al, 2010) and L-DOPA-induced dyskinesia (Subramaniam et al, 2012).…”

“…Ten-to-12-week-old male and female wild-type (WT) and Rasd2 knockout (KO) mice without PGK-neo cassette (Ghiglieri et al, 2015;Sciamanna et al, 2015), derived from mating of heterozygous animals (Rasd2 +/ − ), backcrossed to F11 generation to C57BL/6J strain, were used in this study. Mice were housed in groups in standard cages (29 × 17.5 × 12.5 cm 3 ) at constant temperature (22 ± 1°C) and maintained on a 12/12 h light/dark cycle, with food and water ad libitum.…”