The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease

Huntington's Disease (HD) is an autosomal‐dominant neurodegenerative disorder, characterized by involuntary body movements, cognitive impairment, and psychiatric disorder. The metabotropic glutamate receptor 5 (mGluR5) plays an important role in HD and we have recently demonstrated that mGluR5‐...

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Bibliographic Details
Published in:	Journal of neurochemistry Vol. 147; no. 2; pp. 222 - 239
Main Authors:	Doria, Juliana G., de Souza, Jessica M., Silva, Flavia R., Olmo, Isabella G., Carvalho, Toniana G., Alves‐Silva, Juliana, Ferreira‐Vieira, Talita H., Santos, Jessica T., Xavier, Claudymara Q. S., Silva, Nathalia C., Maciel, Esther M. A., Conn, Peter Jeffrey, Ribeiro, Fabiola M.
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-10-2018
Subjects:	Allosteric properties Animals Brain Cell activation Cognitive ability Conditioning, Classical - drug effects Dendritic plasticity Dendritic spines Dendritic Spines - drug effects Density Gene expression Gene Expression Regulation - drug effects Glutamic acid receptors (metabotropic) Hereditary diseases Huntington Disease - complications Huntington Disease - drug therapy Huntington Disease - psychology Huntington's disease Huntingtons disease Impairment Maturation Memory Memory Disorders - drug therapy Memory Disorders - etiology Memory Disorders - psychology metabotropic glutamate receptor 5 Mice Mice, Inbred C57BL Modulators Molecular modelling Motor Activity - drug effects Neurodegenerative diseases Neuromodulation Neuronal Plasticity - drug effects Neuronal Plasticity - genetics Neurotrophic factors Oxazoles - pharmacology Plasticity Pyridines - pharmacology Receptor, Metabotropic Glutamate 5 - drug effects Receptor, Metabotropic Glutamate 5 - metabolism Recognition, Psychology - drug effects Signal Transduction - drug effects Spine Synapses - drug effects Synaptic density Synaptic plasticity Syntaxin Syntaxin 1 VU0409551 VU0409551 memory synaptic plasticity Huntington's disease metabotropic glutamate receptor 5
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Summary:	Huntington's Disease (HD) is an autosomal‐dominant neurodegenerative disorder, characterized by involuntary body movements, cognitive impairment, and psychiatric disorder. The metabotropic glutamate receptor 5 (mGluR5) plays an important role in HD and we have recently demonstrated that mGluR5‐positive allosteric modulators (PAMs) can ameliorate pathology and the phenotypic signs of a mouse model of HD. In this study, we investigated the molecular mechanisms involved in mGluR5 PAMs effect on memory. Our results demonstrate that subchronic treatment with the mGluR5 PAM VU0409551 was effective in reversing the memory deficits exhibited by BACHD mice, a mouse model for HD. Moreover, VU0409551 treatment stabilized mGluR5 at the cellular plasma membrane of BACHD mice, increasing the expression of several genes important for synaptic plasticity, including c‐Fos, brain‐derived neurotrophic factor, Arc/Arg3.1, syntaxin 1A, and post‐synaptic density‐95. In addition, VU0409551 treatment also increased dendritic spine density and maturation and augmented the number of pre‐synaptic sites. In conclusion, our results demonstrate that VU0409551 triggered the activation of cell signaling pathways important for synaptic plasticity, enhancing the level of dendritic spine maturation and rescuing BACHD memory impairment. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Our results demonstrate that VU0409551 triggers the activation of cell signaling pathways important for synaptic plasticity, enhancing the level of dendritic spine maturation and rescuing BACHD memory impairment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-3042 1471-4159
DOI:	10.1111/jnc.14555