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The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease
Author(s) -
Doria Juliana G.,
de Souza Jessica M.,
Silva Flavia R.,
Olmo Isabella G.,
Carvalho Toniana G.,
AlvesSilva Juliana,
FerreiraVieira Talita H.,
Santos Jessica T.,
Xavier Claudymara Q. S.,
Silva Nathalia C.,
Maciel Esther M. A.,
Conn Peter Jeffrey,
Ribeiro Fabiola M.
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14555
Subject(s) - metabotropic glutamate receptor 5 , dendritic spine , synaptic plasticity , neuroscience , metabotropic glutamate receptor , allosteric modulator , allosteric regulation , neurotrophic factors , biology , glutamate receptor , chemistry , receptor , genetics , hippocampal formation
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/.