Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome

Maurin, Thomas; Melancia, Francesca; Jarjat, Marielle; Castro, Liliana; Costa, Lara; Delhaye, Sébastien; Khayachi, Anouar; Castagnola, Sara; Mota, Élia; Giorgio, Audrey Di; Servadio, Michela; Drozd, Małgorzata; Poupon, Gwénola; Schiavi, Sara; Sardone, Lara Maria; Azoulay, Stéphane; Ciranna, Lucia; Martin, Stéphane; Vincent, Pierre; Trezza, Viviana; Bardoni, Barbara

doi:10.1093/cercor/bhy192

Cited by 36 publications

(65 citation statements)

References 64 publications

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“…Indeed, several mRNAs encoding components of cAMP signaling cascade are target of FMRP (Darnell et al, 2011 ) among which, as above discussed, PDE2A is a major FMRP target (Maurin et al, 2018a ). Importantly, very recent data demonstrate that PDE2A is overactivated in Fmr1 KO mouse brain, leading to reduced cAMP levels, and pharmacological inhibition of PDE2A reverses exaggerated mGluR-LTD in Fmr1 KO hippocampus (Maurin et al, 2018b ).…”

Section: Discussionmentioning

confidence: 99%

Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome

Costa

Sardone

Bonaccorso

et al. 2018

Front. Mol. Neurosci.

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We have previously demonstrated that activation of serotonin 5-HT7 receptors (5-HT7R) reverses metabotropic glutamate receptor-mediated long term depression (mGluR-LTD) in the hippocampus of wild-type (WT) and Fmr1 Knockout (KO) mice, a model of Fragile X Syndrome (FXS) in which mGluR-LTD is abnormally enhanced. Here, we have investigated intracellular mechanisms underlying the effect of 5-HT7R activation using patch clamp on hippocampal slices. Furthermore, we have tested whether in vivo administration of LP-211, a selective 5-HT7R agonist, can rescue learning and behavior in Fmr1 KO mice. In the presence of an adenylate cyclase blocker, mGluR-LTD was slightly enhanced in WT and therefore the difference between mGluR-LTD in WT and Fmr1 KO slices was no longer present. Conversely, activation of adenylate cyclase by either forskolin or Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) completely reversed mGluR-LTD in WT and Fmr1 KO. 5-HT7R activation reversed mGluR-LTD in WT and corrected exaggerated mGluR-LTD in Fmr1 KO; this effect was abolished by blockade of either adenylate cyclase or protein kinase A (PKA). Exposure of hippocampal slices to LP-211 caused an increased phosphorylation of extracellular signal regulated kinase (ERK), an intracellular effector involved in mGluR-LTD, in WT mice. Conversely, this effect was barely detectable in Fmr1 KO mice, suggesting that 5-HT7R-mediated reversal of mGluR-LTD does not require ERK stimulation. Finally, an acute in vivo administration of LP-211 improved novel object recognition (NOR) performance in WT and Fmr1 KO mice and reduced stereotyped behavior in Fmr1 KO mice. Our results indicate that mGluR-LTD in WT and Fmr1 KO slices is bidirectionally modulated in conditions of either reduced or enhanced cAMP formation. Activation of 5-HT7 receptors reverses mGluR-LTD by activation of the cAMP/PKA intracellular pathway. Importantly, a systemic administration of a 5-HT7R agonist to Fmr1 KO mice corrected learning deficits and repetitive behavior. We suggest that selective 5-HT7R agonists might become novel pharmacological tools for FXS therapy.

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Section: Discussionmentioning

confidence: 99%

Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome

Costa

Sardone

Bonaccorso

et al. 2018

Front. Mol. Neurosci.

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“…6 PDE2A was also recently shown to play a role in the physiopathology of fragile X mental retardation syndrome (FXS), and its pharmacological inhibition was proposed as a potential therapeutic approach for FXS. 7 This suggests that PDE2A gain of function would lead to intellectual disability (ID). On the other hand, a homozygous loss-of-function mutation in PDE2A (c.1439A>G; p.Asp480Gly) was recently associated with a early-onset hereditary choreapredominant movement disorder that is also associated with ID.…”

Section: P D E 2 a I N A F A M I L Y W I T H A T Y P I C A Lmentioning

confidence: 99%

A Homozygous Splicing Mutation in PDE2A in a Family With Atypical Rett Syndrome

et al. 2020

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250-mg challenge dose produced a 41% improvement in UPDRS-III with dyskinesia (Supporting Information Table S1). However, she developed FOG on gait initiation, straight walking, doorways, and turning. FOG was associated with rising up onto the toes during straight walking and onto the toe of the outer rotating foot when turning, raising the possibility of a dystonic phenomenon (Video 2). She was diagnosed with on-state FOG. L-dopa was changed to immediate release and fractionated, amantadine 200 mg daily added, and she commenced gait rehabilitation without improvement. Intermittent subcutaneous apomorphine injections were initiated; however, after 6 months' therapy, FOG severity was increased ( Fig. 1), leading to~20 falls a day. Based on previous observations, 4,5 she commenced a 16-hour LCIG infusion. During week 1 of LCIG titration, FOG persisted despite rates that improved parkinsonism while causing dyskinesia, reaffirming on-state FOG. We then performed a rapid infusion titration with hourly increments in the continuous rate of 0.1 to 0.2 mL over 5 hours, starting from 2.1 mL/h, and discovered a higher rate of 3.0 mL/h that led to near-complete resolution of FOG. At 6 months, FOG remained much improved with ≤1 fall per week; however, she still reported FOG when using LCIG extra doses. At 7 months, she converted to 24-hour LCIG with a nocturnal rate of 1.4 mL/h for treatment of nocturnal left foot dystonia. Nocturnal oral L-dopa was no longer required. She reduced her daytime rate from 3.0 to 2.9 mL/h. At 9 months (Video 3), FOG was further reduced, averaging 1 fall every 4 weeks. Pre-LCIG, she had used a wheelchair intermittently for 6 months. She now always walks without aids and no longer avoids escalators or misses lift doors. She experiences two to three occurrences of start hesitation daily and mild, nondisabling dyskinesia of the right leg. Extra doses for mild, nondisabling off periods sometimes trigger transient start hesitation. Hand function is excellent and she recently resumed playing piano.We explored LCIG as treatment for on-state FOG 3 because plasma L-dopa levels with an LCIG infusion are more predictable than oral L-dopa dosing. We surprisingly discovered an interaction between L-dopa infusion rates and FOG behavior that suggested the existence of another FOG subtype (Fig. 1). We suggest the term "triphasic-on" FOG, to denote its presence in both "on" and "supra-on" states, but also the presence of a narrow "on" therapeutic window in the transition between these two states where FOG improves. It is plausible that "triphasic-on" FOG may have been present, but obscured, in at least some of the patients reported on by Espay and colleagues 3 because of the use of a single supra-on challenge dose and the unpredictable plasma L-dopa levels following oral L-dopa. In conclusion, our case suggests that some PD patients with on-state FOG might be able to be treated successfully and implies the existence of additional FOG subtypes.

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“…This indicates an age-dependent and compartmentalized alteration of cAMP enzymes in FXS, suggesting tailored therapeutic approaches. Interestingly, it is found that treatment with PDE2 inhibitor BAY607550 rescues social deficits in infant (postnatal day 10-14) and adolescent (postnatal day 30) Fmr1 KO animals 32 . Although PDE4D expression has not been compared between normal and FXS samples, chronic treatment with PDE4D negative allosteric modulator (NAM) BPN14770 improves behavioral symptoms associated with social interaction and perseveration 44 .…”

Section: Discussionmentioning

confidence: 99%

Carbamazepine restores neuronal signaling, protein synthesis and cognitive function in a mouse model of fragile X syndrome

Ding

Zhang

Feng

et al. 2020

Preprint

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Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment.

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Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome

Cited by 36 publications

References 64 publications

Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome

Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome

A Homozygous Splicing Mutation in PDE2A in a Family With Atypical Rett Syndrome

Carbamazepine restores neuronal signaling, protein synthesis and cognitive function in a mouse model of fragile X syndrome

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