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

Ghiglieri V, Napolitano F, Pelosi B, Schepisi C, Migliarini S, Di Maio A, Pendolino V, Mancini M, Sciamanna G, Vitucci D, Maddaloni G, Giampà C, Errico F, Nisticò R, Pasqualetti M, Picconi B, Usiello A - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Philosophy, Human, Social, and Educational Sciences, University of Perugia, Perugia, Italy [2] Fondazione Santa Lucia IRCCS, Rome, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

D1R and A2AR-dependent behavioral responses in Rhes mutant mice.(A,B) Locomotor activity induced in male (A) and female (B) WT and KO mice by SKF 81297 (1.25 mg/kg: WT, n = 15 males, n = 14 females; KO, n = 13 males, n = 14 females; 2.5 mg/kg: WT, n = 21 males, n = 21 females; KO, n = 23 males, n = 19 females) or in Veh-treated group (WT, n = 21/gender; KO, n = 22 males, n = 21 females). (C,D) Cataleptic effect of Hal in male (C) and female (D) WT and KO mice (0.1 mg/kg: n = 8/genotype and gender; 0.25 mg/kg: n = 8/genotype and gender; 0.5 mg/kg: WT, n = 13 males, n = 8 females; KO, n = 13 males, n = 8 females) or Veh-treated group (WT, n = 8 males, n = 5 females; KO, n = 8 males, n = 5 females). *p < 0.05, **p < 0.01, compared with Hal-treated WT mice. (E) Effect of adenosine A2AR blockade by CSC treatment (2.5 mg/kg) on haloperidol-dependent catalepsy in female WT and KO mice. Animals were treated with CSC plus Hal (WT, n = 7; KO, n = 6) or Hal (WT, n = 7; KO, n = 6) and analyzed 60 min after haloperidol injection. **p < 0.01, compared with Hal-treated group. (F,G) Locomotor activity in male (F) and female (G) WT and KO mice induced by caffeine 7.5 mg/kg (WT, n = 11 males, n = 18 females; KO, n = 12 males, n = 18 females), compared to Veh-treated mice (WT, n = 10 males, n = 11 females; KO n = 10/gender). All data are expressed as mean ± SEM. Genotypes are as indicated.
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f6: D1R and A2AR-dependent behavioral responses in Rhes mutant mice.(A,B) Locomotor activity induced in male (A) and female (B) WT and KO mice by SKF 81297 (1.25 mg/kg: WT, n = 15 males, n = 14 females; KO, n = 13 males, n = 14 females; 2.5 mg/kg: WT, n = 21 males, n = 21 females; KO, n = 23 males, n = 19 females) or in Veh-treated group (WT, n = 21/gender; KO, n = 22 males, n = 21 females). (C,D) Cataleptic effect of Hal in male (C) and female (D) WT and KO mice (0.1 mg/kg: n = 8/genotype and gender; 0.25 mg/kg: n = 8/genotype and gender; 0.5 mg/kg: WT, n = 13 males, n = 8 females; KO, n = 13 males, n = 8 females) or Veh-treated group (WT, n = 8 males, n = 5 females; KO, n = 8 males, n = 5 females). *p < 0.05, **p < 0.01, compared with Hal-treated WT mice. (E) Effect of adenosine A2AR blockade by CSC treatment (2.5 mg/kg) on haloperidol-dependent catalepsy in female WT and KO mice. Animals were treated with CSC plus Hal (WT, n = 7; KO, n = 6) or Hal (WT, n = 7; KO, n = 6) and analyzed 60 min after haloperidol injection. **p < 0.01, compared with Hal-treated group. (F,G) Locomotor activity in male (F) and female (G) WT and KO mice induced by caffeine 7.5 mg/kg (WT, n = 11 males, n = 18 females; KO, n = 12 males, n = 18 females), compared to Veh-treated mice (WT, n = 10 males, n = 11 females; KO n = 10/gender). All data are expressed as mean ± SEM. Genotypes are as indicated.

Mentions: Here we investigated the gender effect of Rhes deletion on behavioral responses induced by DA and adenosine drugs. At all doses tested, the DA D1R agonist, SKF 81297, similarly enhanced horizontal motor activity in males of both genotypes (Fig. 6A; three-way ANOVA with repeated measures, treatment effect: 1.25 mg/kg, F(1,335) = 33.633, p < 0.0001; 2.5 mg/kg, F(1,415) = 86.567, p < 0.0001). Likewise, SKF 81297 treatment in females also induced hyperlocomotion in both genotypes at either dose tested (Fig. 6B; 1.25 mg/kg, F(1,330) = 10.644, p = 0.0018; 2.5 mg/kg, F(1,390) = 14.095, p = 0.0003). However, female mutants showed a significant higher hyperactivity at 2.5 mg/kg drug dose (genotype effect, F(1,390) = 5.456, p = 0.0221), compared to control treated animals.


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

Ghiglieri V, Napolitano F, Pelosi B, Schepisi C, Migliarini S, Di Maio A, Pendolino V, Mancini M, Sciamanna G, Vitucci D, Maddaloni G, Giampà C, Errico F, Nisticò R, Pasqualetti M, Picconi B, Usiello A - Sci Rep (2015)

D1R and A2AR-dependent behavioral responses in Rhes mutant mice.(A,B) Locomotor activity induced in male (A) and female (B) WT and KO mice by SKF 81297 (1.25 mg/kg: WT, n = 15 males, n = 14 females; KO, n = 13 males, n = 14 females; 2.5 mg/kg: WT, n = 21 males, n = 21 females; KO, n = 23 males, n = 19 females) or in Veh-treated group (WT, n = 21/gender; KO, n = 22 males, n = 21 females). (C,D) Cataleptic effect of Hal in male (C) and female (D) WT and KO mice (0.1 mg/kg: n = 8/genotype and gender; 0.25 mg/kg: n = 8/genotype and gender; 0.5 mg/kg: WT, n = 13 males, n = 8 females; KO, n = 13 males, n = 8 females) or Veh-treated group (WT, n = 8 males, n = 5 females; KO, n = 8 males, n = 5 females). *p < 0.05, **p < 0.01, compared with Hal-treated WT mice. (E) Effect of adenosine A2AR blockade by CSC treatment (2.5 mg/kg) on haloperidol-dependent catalepsy in female WT and KO mice. Animals were treated with CSC plus Hal (WT, n = 7; KO, n = 6) or Hal (WT, n = 7; KO, n = 6) and analyzed 60 min after haloperidol injection. **p < 0.01, compared with Hal-treated group. (F,G) Locomotor activity in male (F) and female (G) WT and KO mice induced by caffeine 7.5 mg/kg (WT, n = 11 males, n = 18 females; KO, n = 12 males, n = 18 females), compared to Veh-treated mice (WT, n = 10 males, n = 11 females; KO n = 10/gender). All data are expressed as mean ± SEM. Genotypes are as indicated.
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Related In: Results  -  Collection

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f6: D1R and A2AR-dependent behavioral responses in Rhes mutant mice.(A,B) Locomotor activity induced in male (A) and female (B) WT and KO mice by SKF 81297 (1.25 mg/kg: WT, n = 15 males, n = 14 females; KO, n = 13 males, n = 14 females; 2.5 mg/kg: WT, n = 21 males, n = 21 females; KO, n = 23 males, n = 19 females) or in Veh-treated group (WT, n = 21/gender; KO, n = 22 males, n = 21 females). (C,D) Cataleptic effect of Hal in male (C) and female (D) WT and KO mice (0.1 mg/kg: n = 8/genotype and gender; 0.25 mg/kg: n = 8/genotype and gender; 0.5 mg/kg: WT, n = 13 males, n = 8 females; KO, n = 13 males, n = 8 females) or Veh-treated group (WT, n = 8 males, n = 5 females; KO, n = 8 males, n = 5 females). *p < 0.05, **p < 0.01, compared with Hal-treated WT mice. (E) Effect of adenosine A2AR blockade by CSC treatment (2.5 mg/kg) on haloperidol-dependent catalepsy in female WT and KO mice. Animals were treated with CSC plus Hal (WT, n = 7; KO, n = 6) or Hal (WT, n = 7; KO, n = 6) and analyzed 60 min after haloperidol injection. **p < 0.01, compared with Hal-treated group. (F,G) Locomotor activity in male (F) and female (G) WT and KO mice induced by caffeine 7.5 mg/kg (WT, n = 11 males, n = 18 females; KO, n = 12 males, n = 18 females), compared to Veh-treated mice (WT, n = 10 males, n = 11 females; KO n = 10/gender). All data are expressed as mean ± SEM. Genotypes are as indicated.
Mentions: Here we investigated the gender effect of Rhes deletion on behavioral responses induced by DA and adenosine drugs. At all doses tested, the DA D1R agonist, SKF 81297, similarly enhanced horizontal motor activity in males of both genotypes (Fig. 6A; three-way ANOVA with repeated measures, treatment effect: 1.25 mg/kg, F(1,335) = 33.633, p < 0.0001; 2.5 mg/kg, F(1,415) = 86.567, p < 0.0001). Likewise, SKF 81297 treatment in females also induced hyperlocomotion in both genotypes at either dose tested (Fig. 6B; 1.25 mg/kg, F(1,330) = 10.644, p = 0.0018; 2.5 mg/kg, F(1,390) = 14.095, p = 0.0003). However, female mutants showed a significant higher hyperactivity at 2.5 mg/kg drug dose (genotype effect, F(1,390) = 5.456, p = 0.0221), compared to control treated animals.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Philosophy, Human, Social, and Educational Sciences, University of Perugia, Perugia, Italy [2] Fondazione Santa Lucia IRCCS, Rome, Italy.

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.

No MeSH data available.


Related in: MedlinePlus