Untersuchungen zur Rolle der metabotropen Glutamatrezeptoren als Modulatoren des Plastizitäts-Pathologie-Kontinuum im Hippokampus der Ratte
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 lomg-term potentiation (LTP) and are less important for long-term depression (LTD), exactly the opposite is true for group II and II 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 mGluRs 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. MGluR5 stood out as the mGluR that may prove essential for all kinds of hippocampusdependent cognitive processing. Although both group I mGluRs, namely mGluR1 and mGluR5, were found to be essentially required for persistent LTP and long-term spatial memory, our investigations of mGluR5 revealed an abundance of roles for this receptor in hippocampal function. On the one hand it appears to drive neuronal network oscillations that reflect information processing and which occur as a consequence of the induction of LTP. On the other hand it regulates the expression of hippocampal mGluR1, and appears to be intrinsically involved in regulating the dynamic range for LTP in the hippocampus. Thus inhibiting mGluR5 not only disrupts network oscillations, it also impairs learning and changes the magnitude of LTP elicited by electrical stimulation. Taken together with the finding that activation of this group I mGluRs induces chemical LTD in the hippocampus that is protein synthesis dependent, this suggests that group I mGluRs and in particular mGluR5 may play a pivotal role in integrating synaptic information such that memories can result.
Publications
- (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. 2005;49 Suppl 1:1-12
Poschel B, 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.Eur J Neurosci. 21:411-421
Naie K, 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. 15:1414-1423
Poschel B, Wroblewska B, Heinemann U, Manahan-Vaughan D
- (2005) The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity. Cereb Cortex. 15:1703-1713
Manahan-Vaughan D, Braunewell KH
- (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
Naie K, Tsanov M, Manahan-Vaughan, D
- (2007) Group III but not group II metabotropic glutamate receptors are involved in spatial memory processing in the morris water maze. Eur J Neurosci. 26: 1166-1172
Altinbilek, B and 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
Poschel B, Manahan-Vaughan D
