Investigations of the role of metabotropic glutamate receptors in cognition and brain disease

• Applicant: Professorin Dr. Denise Manahan-Vaughan
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2005 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5448516

• Final Report Year: 2008

Final Report Abstract

This project has yielded substantial new insights into the role of metabotropic glutamate receptors (mGluRs) in synaptic information storage and learning within the hippocampus, the primary learning organ of the mammalian brain. We established that very marked differences exist in the contribution of mGluRs to both synaptic plasticity and the acquisition of spatial memories. Whereas phospholipase C-coupled group I mGluRs play a critical role in long-term potentiation (LTP) and are less important for long-term depression (LTD), exactly the opposite is true for group ll and ll mGluRs that are adenylyl cyclase (AC) coupled. Despite this, all groups of mGluR are critically required for long-term spatial memory, suggesting that a cooperation between LTP and LTD may be required for the generation of persistent memories. Considering that AC-coupled mGluRs are critically required for longterm memory, it was surprising to find that in the dentate gyrus (a key information input structure within the hippocampus) no form of mGluR-dependent LTD requires protein synthesis. This observation was unexpected given the widespread belief that long-term memory requires the synthesis of new proteins at the synaptic level. Thus neither group II mGluR-dependent LTD elicited by low frequency afferent stimulation, nor LTD elicited by activation of either group II or group III mGtuRs required protein synthesis even though the synaptic depression persisted for over 24h. This finding, taken together with the observation that blockade of these receptors prevents long-term memory necessitates a rethink in the assumed indispensibilty of protein synthsis for long-term memory.

Publications

• Manahan-Vaughan D, Braunewell KH. (2005) The metabotropic glutamate receptor, mGluRS, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity.Cereb Cortex. 15:1703-13.
  
  
• Naie K, Manahan-Vaughan D. (2005) Investigations of the protein synthesis dependency of niGluR-induced long-term depression in the dentate gyrus of freely moving rats. Neurophannacology. 49 Suppl 1:35-44.
  
  
• Naie K, Gundimi S, Siegmund H, Heinemann U, Manahan-Vaughan D. (2006) Group III metabotropic glutamate receptor-mediated, chemically induced long-term depression differentially affects cell viability in the hippocampus.Eur J Pharmacol. 535(1-3):104-13.
  
  
• Poschel B, Manahan-Vaughan D. (2007) Persistent (>24h) long-term depression in the dentate gyrus of freely moving rats is not dependent on activation of NMDA receptors, L-type voltage-gated calcium channels or protein synthesis. Neuropharmacology. 52:46-54.
  
  
• Bikbaev A, Neyman S, Ngomba R, Nicoletti F, Conn PJ. Manahan-Vaughan D (2008) The metabotropic glutamate receptor, mGluRS, mediates the functional interaction between late- LTP, hippocampal network activity, and leaming by a mechanism involving regulation of mGluRI expression. PloS One. 13(5):e2155.
  
  
• Neyman S, Manahan-Vaughan D (2008) Metabotropic glutamate receptor 1 (mGtuRI) and 5 (mGluRS) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro Eur J Neurosci. 27:1345-52.
  
  
• Altinbilek B, Manahan-Vaughan D (2007) Antagonism of group III metabotropic glutamate receptors results in impairment of LTD but not LTP in the hippocampal CA1 region, and prevents long-tenn spatial memory. EurJ Neurosci. 26:1166-1172.
  
  
• Bikbaev A, Manahan-Vaughan D (2007) Hippocampal network activity is transiently altered by induction of long-term potentiation In the dentate gyrus of freely behaving rats. Front. Beh. Neurosci 1(2):1-7
  
  
• Bikbaev A, Manahan-Vaughan D (2008) Relationship of hippocampal theta and gamma oscillations to potentiation of synaptic transmission. Front Neurosci. 1:56-63.
  
  
• Kulla, A. and Manahan-Vaughan, D (2007) Modulation by group 1 metabotropic glutamate receptors of depotentiation in the dentate gyrus of freely moving rats. Hippocampus 18:48-54.
  
  
• Naie K, Manahan-Vaughan D. (2005) Pharmacological antagonism of metabotropic glutamate receptor 1 regulates long-term potentiation and spatial reference memory in the dentate gyrus of freely moving rats via N-methyl-D-aspartate and metabotropic glutamate receptor-dependent mechanisms. EurJ Neurosci. 21:411-21.
  
  
• Naie K, Tsanov M, Manahan-Vaughan,D (2007) Group I metabotropic glutamate receptors enable two distinct forms of LTD in the rat dentate gyrus in vivo. Eur J Neurosci. 25:3264- 32757.
  
  
• Poschel B, Manahan-Vaughan D. (2005) Group II mGluR-induced long term depression in the dentate gyrus in vivo Is NMDA receptor-Independent and does not require protein synthesis. Neuropharmacology. 49 Suppl 1:1-12.
  
  
• Poschel B, Wroblewska B, Heinemann U, Manahan-Vaughan D. (2005) The metabotropic glutamate receptor mGluR3 is critically required for hippocampal long-term depression and modulates long-term potentiation in the dentate gyrus of freely moving rats. Cereb Cortex. 15:1414-23.