The Brain Cytoplasmic RNA BC1 Regulates Dopamine D<sub>2</sub>Receptor-Mediated Transmission in the Striatum

Centonze, Diego; Rossi, Silvia; Napoli, Ilaria; Mercaldo, Valentina; Lacoux, Caroline; Ferrari, Francesca; Ciotti, Maria Teresa; Chiara, Valentina De; Prosperetti, Chiara; Maccarrone, Mauro; Fezza, Filomena; Calabresi, Paolo; Bernardi, Giorgio; Bagni, Claudia

doi:10.1523/jneurosci.0548-07.2007

Cited by 46 publications

(41 citation statements)

References 41 publications

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“…Several studies suggested modulation of GABAergic inhibitory signaling as an alternative or additional therapeutic strategy in FXS: Fmr1 KO mice show impaired GABAergic inhibition in several different brain areas (Centonze et al, 2007;Curia et al, 2009), which is in line with the notion that the absence of FMRP converts neurons into a 'hyperexcitable' state. Impaired GABAergic signaling in FXS might partially be caused by decreased expression of GABA receptors in these brain areas (El Idrissi et al, 2005;D'Hulst et al, 2006;Adusei et al, 2010).…”

Section: Altered Signaling Of Other Membrane Receptorssupporting

confidence: 60%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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Section: Altered Signaling Of Other Membrane Receptorssupporting

confidence: 60%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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“…Mice lacking fmr1 (FMRP-KO), BC1 RNA (BC1-KO), and both fmr1 and BC1 RNA (FMRP-BC1-KO) were employed along with their respective, age-matched wild-type (WT) strains (2-3 months old), as already reported (Centonze et al, 2007a(Centonze et al, , 2008. Corticostriatal coronal slices (200 mm) were prepared from brain blocks with the use of a vibratome .…”

Section: Methodsmentioning

confidence: 99%

Abnormal mGlu 5 Receptor/Endocannabinoid Coupling in Mice Lacking FMRP and BC1 RNA

Maccarrone

Rossi

Bari

et al. 2010

Neuropsychopharmacol

110

103

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Transcriptional silencing of the gene encoding the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP acts as a translational repressor at central synapses, and molecular and synaptic plasticity studies have shown that the absence of this protein alters metabotropic glutamate 5 receptors (mGlu5Rs)-mediated signaling. In the striatum of mice lacking FMRP, we found enhanced activity of diacylglycerol lipase (DAGL), the enzyme limiting 2-arachidonoylglicerol (2-AG) synthesis, associated with altered sensitivity of GABA synapses to the mobilization of this endocannabinoid by mGlu5R stimulation with DHPG. Mice lacking another repressor of synaptic protein synthesis, BC1 RNA, also showed potentiated mGlu5R-driven 2-AG responses, indicating that both FMRP and BC1 RNA act as physiological constraints of mGlu5R/endocannabinoid coupling at central synapses. The effects of FMRP ablation on DAGL activity and on DHPG-mediated inhibition of GABA synapses were enhanced by simultaneous genetic inactivation of FMRP and BC1 RNA. In double FMRP and BC1 RNA lacking mice, striatal levels of 2-AG were also enhanced compared with control animals and to single mutants. Our data indicate for the first time that mGlu5R-driven endocannabinoid signaling in the striatum is under the control of both FMRP and BC1 RNA. The abnormal mGlu5R/2-AG coupling found in FMRP-KO mice emphasizes the involvement of mGlu5Rs in the synaptic defects of FXS, and identifies the modulation of the endocannabinoid system as a novel target for the treatment of this severe neuropsychiatric disorder.

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“…Immunofluorescence was performed as previously described (6). FISH and immunofluorescence on striatal tissue was performed as previously described (38).…”

Section: Fish and Immunofluorescence On Striatal Tissue And Striatal mentioning

confidence: 99%

“…The interaction with BC1 RNA seems to be crucial for its involvement in translation regulation because this small noncoding RNA has the potential to base pair to neuronal target mRNAs, connecting the mRNAs and FMRP (14,40,60,61). BC1 RNA, as FMRP, is efficiently transported along dendrites and axons (38,(62)(63)(64)(65) through a process requiring intact microtubules. In vitro, BC1 has been shown to act as translational repressor of chimeric mRNAs (66,67).…”

Section: Bc1 Rna In the Control Of Striatal Synaptic Transmissionmentioning

confidence: 99%

Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome

Centonze

Rossi

Mercaldo

et al. 2008

Biological Psychiatry

150

134

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The Brain Cytoplasmic RNA BC1 Regulates Dopamine D₂Receptor-Mediated Transmission in the Striatum

Cited by 46 publications

References 41 publications

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Abnormal mGlu 5 Receptor/Endocannabinoid Coupling in Mice Lacking FMRP and BC1 RNA

Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome

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The Brain Cytoplasmic RNA BC1 Regulates Dopamine D2Receptor-Mediated Transmission in the Striatum

Cited by 46 publications

References 41 publications

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Abnormal mGlu 5 Receptor/Endocannabinoid Coupling in Mice Lacking FMRP and BC1 RNA

Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome

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The Brain Cytoplasmic RNA BC1 Regulates Dopamine D₂Receptor-Mediated Transmission in the Striatum