title: 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.
authors.affiliation: Department of Philosophy, Human, Social, and Educational Sciences, University of Perugia, Perugia, Italy.|Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pelosi
authors.affiliation: Fondazione Santa Lucia IRCCS, Rome, Italy.|Department of Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Schepisi
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Migliarini
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Maio
authors.affiliation: Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pendolino
authors.affiliation: Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Fondazione Santa Lucia IRCCS, Rome, Italy.|Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciamanna
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.|Dipartimento di Scienze Motorie e del Benessere DiSMeB, University of Naples "Parthenope", Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vitucci
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Maddaloni
authors.affiliation: Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Errico
authors.affiliation: Fondazione Santa Lucia IRCCS, Rome, Italy.|Department of Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.|Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pasqualetti
authors.affiliation: Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.|Department of Environmental Sciences, Second University of Naples, Naples, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D013181:Cortical Spreading Depression / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics*; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009154:Mutation; D009473:Neuronal Plasticity / Q000235:genetics; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse; D004298:Dopamine