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Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice
Antonella Ferrante1, Zaira Boussadia1, Antonella Borreca2,3
1National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Abstract:
In fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A2A receptors (A2ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A2A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking A2ARs might normalize the mGlu5R-mediated effects of FXS. To study the cross-talk between A2A and mGlu5 receptors in the absence of FMRP, we performed extracellular electrophysiology experiments in hippocampal slices of Fmr1 KO mouse. The depression of field excitatory postsynaptic potential (fEPSPs) slope induced by the mGlu5R agonist CHPG was completely blocked by the A2AR antagonist ZM241385 and strongly potentiated by the A2AR agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic A2AR blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an A2AR antagonist. We found that hippocampal DHPG-induced long-term depression (LTD), which is abnormally increased in FXS mice, was restored to the WT level. Furthermore, istradefylline corrected aberrant dendritic spine density, specific behavioral alterations, and overactive mTOR, TrkB, and STEP signaling in Fmr1 KO mice. Finally, we identified A2AR mRNA as a target of FMRP. Our results show that the pharmacological blockade of A2ARs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other A2AR-related downstream targets.
Insights
Blocking adenosine A2A receptors (A2ARs) partially reverses fragile X syndrome (FXS) phenotypes in mice. This treatment normalizes metabotropic glutamate receptor 5 (mGlu5R) signaling and corrects behavioral and molecular deficits in FMRP-deficient mice.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Fragile X syndrome (FXS) is characterized by the absence of fragile X mental retardation protein (FMRP), leading to exaggerated metabotropic glutamate receptor 5 (mGlu5R) signaling.
- Adenosine A2A receptors (A2ARs) modulate neuronal function and interact with mGlu5Rs in the hippocampus, suggesting a potential therapeutic target for FXS.
- Previous studies indicate a synaptic interaction between A2A and mGlu5 receptors, hinting that A2A receptor blockade might ameliorate FXS-related abnormalities.
Purpose of the Study:
- To investigate the cross-talk between A2A and mGlu5 receptors in the absence of FMRP.
- To determine if chronic blockade of A2A receptors can reverse FXS phenotypes in a mouse model.
- To identify A2A receptors as a potential therapeutic target for FXS.
Main Methods:
- Extracellular electrophysiology was used to study hippocampal slices from Fmr1 knockout (KO) mice.
- Electrophysiological responses to mGlu5R agonist (CHPG) were assessed in the presence of A2A receptor modulators.
- Fmr1 KO mice were treated with an A2A receptor antagonist (istradefylline) to evaluate phenotypic reversal, including long-term depression (LTD), dendritic spine density, behavior, and signaling pathways.
Main Results:
- A2A receptor antagonism blocked mGlu5R-induced synaptic depression in Fmr1 KO mice, while agonism potentiated it, indicating increased functional coupling.
- Chronic treatment with istradefylline restored normal hippocampal LTD, corrected aberrant dendritic spine density, and ameliorated behavioral deficits in Fmr1 KO mice.
- Istradefylline treatment also normalized overactive mTOR, TrkB, and STEP signaling pathways and identified A2A receptor mRNA as an FMRP target.
Conclusions:
- Pharmacological blockade of A2A receptors partially restores multiple FXS phenotypes in Fmr1 KO mice.
- A2A receptor antagonists may represent a viable therapeutic strategy for FXS by modulating mGlu5R signaling and downstream targets.
- The interaction between A2A and mGlu5 receptors, and A2A receptor's role as an FMRP target, are critical in FXS pathophysiology.
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