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A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Published on: May 22, 2019
Epac-mediated cAMP-signalling in the mouse model of Rett Syndrome
S L Mironov1, E Y Skorova, S Kügler
1DFG-Center of Molecular Physiology of the Brain, Germany. smirono@gwdg.de
Insights
Rett Syndrome (RTT) is linked to abnormal cAMP levels in the brain, impacting neuronal development and respiratory control. Restoring cAMP levels with PDE4 inhibition improved neuronal function in a mouse model.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Rett Syndrome (RTT) is a neurodevelopmental disorder associated with synaptogenesis and neuronal circuitry deficits.
- Cyclic adenosine monophosphate (cAMP) is crucial for neuronal outgrowth, plasticity, and regeneration.
Purpose of the Study:
- To investigate cAMP homeostasis in the pre-Bötzinger complex during early postnatal development in a mouse model of Rett Syndrome (MeCP2-/y mice).
- To explore the role of cAMP signaling, specifically Epac, in the pathophysiology of RTT and its impact on respiratory circuits.
Main Methods:
- Quantified cAMP levels and fluctuations in neurons of MeCP2-/y mice using a targeted Epac1-camps sensor.
- Utilized pharmacological agents like rolipram (PDE4 inhibitor) and 8-pCPT (Epac activator) to modulate cAMP levels and signaling.
- Assessed neuronal process elongation and neuronal bursting activity in response to cAMP modulation.
Main Results:
- MeCP2-/y mice exhibited lower resting cAMP levels and reduced amplitude/faster time-course of cAMP transients compared to wild-type.
- Inhibition of phosphodiesterase PDE4 normalized cAMP levels and transients in mutant mice.
- Elevated cAMP levels, particularly via Epac activation, promoted neuronal outgrowth and normalized bursting activity in pre-Bötzinger complex neurons of RTT models.
Conclusions:
- Disturbances in cAMP homeostasis in RTT mouse models lead to inadequate Epac signaling.
- Defective cAMP-Epac signaling contributes to the aberrant development of respiratory circuits, potentially causing irregular breathing in RTT.
- Targeting cAMP pathways, especially Epac, may offer therapeutic strategies for RTT-associated respiratory dysfunction.
Abstract:
Rett Syndrome (RTT) is a neurodevelopmental disease thought to be caused by deficits in synaptogenesis and neuronal circuitry. cAMP is one of the key factors for neuronal outgrowth, plasticity and regeneration. We examined its homeostasis in RTT during early postnatal development of the essential part of the respiratory network, pre-Bötzinger complex. Using targeted expression of Epac1-camps sensor in neurons we quantified cAMP levels and their fluctuations in MeCP2-/y mice, an established model of RTT. Resting cAMP levels in the mutant were smaller than in the wild-type. cAMP transients elicited by depolarisation and stimulation of adenylate cyclase had also smaller amplitudes and faster time-courses. The anomalies in MeCP2 -/y mice were removed after inhibition of phosphodiesterase PDE4 with rolipram. Brief cAMP elevations triggered elongation of neuronal processes that was significantly bigger in the wild-type. The effects were observed after inhibition of protein kinase A and mimicked by activation of a guanine nucleotide exchange factor, Epac, with 8-(4-Chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8-pCPT). The agonist reinforced bursting in preBötC neurons in the mutant and converted it to the wild-type. All actions of 8-pCPT were not reproduced by its non-active analogue and abolished by Epac signalling inhibitor Brefeldin A. We propose that disturbances in cAMP homeostasis in MeCP2 -/y mice can lead to inadequate Epac signalling. Concomitant defective development of respiratory circuits may be responsible for irregular breathing activity in RTT.
