Huntington’ s Disease and Group I Metabotropic Glutamate Receptors Fabiola M. Ribeiro & Rita G. W. Pires & Stephen S. G. Ferguson Received: 15 October 2010 / Accepted: 15 November 2010 / Published online: 9 December 2010 # Springer Science+Business Media, LLC 2010 Abstract Huntington’ s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary body movement, cognitive impairment and psychiatric disturbance. A polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein is the genetic cause of HD. Htt protein interacts with a wide variety of proteins, and htt mutation causes cell signaling alterations in various neurotransmitter systems, including dopaminergic, glutamatergic, and cannabinoid systems, as well as trophic factor systems. This review will overview recent findings concerning htt-promoted alterations in cell signaling that involve different neurotransmitters and trophic factor systems, especially involving mGluR1/5, as glutamate plays a crucial role in neuronal cell death. The neuronal cell death that takes place in the striatum and cortex of HD patients is the most important factor underlying HD progression. Metabotropic glutamate recep- tors (mGluR1 and mGluR5) have a very controversial role in neuronal cell death and it is not clear whether mGluR1/5 activation either protects or exacerbates neuronal death. Thus, understanding how mutant htt protein affects gluta- matergic receptor signaling will be essential to further establish a role for glutamate receptors in HD and develop therapeutic strategies to treat HD. Keywords Huntington’ s disease . htt protein . Metabotropic glutamate receptor (mGluR) Abbreviations DHPG (S)-3,5-dihydroxylphenylglycine AMPA Alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid CNS Central nervous system PLC Phospholipase C ERK Extracellular signal-regulated kinase MAPK Mitogen-activated protein kinase GPCR G protein-coupled receptor InsP Inositol phosphate AD Alzheimer ’ s disease HD Huntington’ s disease htt Huntingtin protein IP3 Inositol-1,4,5-triphosphate mGluR Metabotropic glutamate receptor NMDAR N-methyl-D-aspartate receptor PKC Protein kinase C PLCβ1 Phospholipase Cβ1 PLD Phospholipase D PLA 2 Phospholipase A 2 PI3K Phosphoinositide 3-kinase PDK1 Phosphoinositide-dependent kinase PIKE PI3K enhancer MSNs Medium-sized spiny neurons PPE Preproenkephalin DARPP-32 Dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa F. M. Ribeiro Departamento de Bioquimica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil R. G. W. Pires Departamento de Ciencias Fisiologicas, CCS, Universidade Federal do Espirito Santo, Vitoria, Brazil S. S. G. Ferguson (*) J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, Robarts Research Institute and Department of Physiology and Pharmacology, University of Western Ontario, 100 Perth Drive, London, ON, Canada N6A 5K8 e-mail: ferguson@robarts.ca Mol Neurobiol (2011) 43:1–11 DOI 10.1007/s12035-010-8153-1