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Updated: Jul 24, 2025
Strategies for Assessing Autistic-Like Behaviors in Mice
Published on: September 20, 2024
Blunted type-5 metabotropic glutamate receptor-mediated polyphosphoinositide hydrolysis in two mouse models of
Luisa Di Menna1, Rosamaria Orlando2, Giovanna D'Errico1
1IRCCS Neuromed, Pozzilli, Italy.
Abstract:
The involvement of the mGlu5 receptors in the pathophysiology of several forms of monogenic autism has been supported by numerous studies following the seminal observation that mGlu5 receptor-dependent long-term depression was enhanced in the hippocampus of mice modeling the fragile-X syndrome (FXS). Surprisingly, there are no studies examining the canonical signal transduction pathway activated by mGlu5 receptors (i.e. polyphosphoinositide - PI - hydrolysis) in mouse models of autism. We have developed a method for in vivo assessment of PI hydrolysis based on systemic injection of lithium chloride followed by treatment with the selective mGlu5 receptor PAM, VU0360172, and measurement of endogenous inositolmonophosphate (InsP) in brain tissue. Here, we report that mGlu5 receptor-mediated PI hydrolysis was blunted in the cerebral cortex, hippocampus, and corpus striatum of Ube3am-/p+ mice modeling Angelman syndrome (AS), and in the cerebral cortex and hippocampus of Fmr1 knockout mice modeling FXS. In vivo mGlu5 receptor-mediated stimulation of Akt on threonine 308 was also blunted in the hippocampus of FXS mice. These changes were associated with a significant increase in cortical and striatal Homer1 levels and striatal mGlu5 receptor and Gαq levels in AS mice, and with a reduction in cortical mGlu5 receptor and hippocampal Gαq levels, and an increase in cortical phospholipase-Cβ and hippocampal Homer1 levels in FXS mice. This is the first evidence that the canonical transduction pathway activated by mGlu5 receptors is down-regulated in brain regions of mice modeling monogenic autism.
Insights
This study reveals that the mGluR5 receptor
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- mGluR5 receptors are implicated in the pathophysiology of monogenic autism.
- Previous research noted enhanced mGluR5-dependent long-term depression in fragile X syndrome (FXS) mouse models.
- The canonical signal transduction pathway of mGluR5 receptors, polyphosphoinositide (PI) hydrolysis, has not been studied in autism mouse models.
Purpose of the Study:
- To investigate the in vivo assessment of mGluR5 receptor-mediated PI hydrolysis in mouse models of Angelman syndrome (AS) and FXS.
- To examine the downstream signaling pathway, including Akt stimulation, in these autism models.
- To explore associated changes in key molecular components like Homer1, mGluR5, Gαq, and phospholipase-Cβ.
Main Methods:
- Developed a novel in vivo method for assessing PI hydrolysis using lithium chloride and a selective mGluR5 receptor positive allosteric modulator (PAM).
- Measured endogenous inositolmonophosphate (InsP) levels in brain tissue.
- Analyzed mGluR5-mediated Akt stimulation and levels of Homer1, mGluR5, Gαq, and phospholipase-Cβ in specific brain regions.
Main Results:
- mGluR5-mediated PI hydrolysis was significantly blunted in the cerebral cortex, hippocampus, and corpus striatum of AS mice.
- Reduced mGluR5-mediated PI hydrolysis was observed in the cerebral cortex and hippocampus of FXS mice.
- Downstream signaling, including Akt stimulation, was also blunted in FXS mice; specific molecular changes in Homer1, mGluR5, Gαq, and phospholipase-Cβ were noted in both AS and FXS models.
Conclusions:
- This study provides the first evidence of down-regulation in the canonical mGluR5 receptor transduction pathway in brain regions of mice modeling monogenic autism.
- These findings highlight a potential common molecular deficit across different forms of monogenic autism.
- The developed in vivo method offers a valuable tool for studying mGluR5 signaling in neurological disorders.
