Age-associated impairments in cognitive functions are well documented in elderly individuals. Therefore, understanding the neurobiological basis of memory deficits in aging is important in the development of effective treatments. Although considerable evidence indicates that the metabotropic glutamate receptors (mGluRs) in the hippocampus have an essential role in learning and memory processes, the subtype-specific involvement of mGluRs in distinct behavioral paradigms remained to be solved. The proposed research seeks to identify the mGluR subtype required for memory formation in passive avoidance learning. Selective mGluR antagonists will be infused into the hippocampus after training the rats in a one-trial inhibitory avoidance paradigm and retention latency will be measured 24 hours later. It is predicted that among the mGluR ligands proposed to be studied, only the mGluR5 antagonist will cause a memory deficit. We will also determine whether the mGluR coupled mitogen-activated protein kinase (MAPK) cascade involved in this effect by testing the antagonist's ability to inhibit the posttraining activation of MAPK by using quantitative Western blot analysis. The preliminary data supporting this application demonstrate a significant decrease in the expression of mGluR5 in the hippocampus in aged animals. Age-differences in the expression and/or coupling of mGluR5 play a critical role in the decline of long-term retention of inhibitory avoidance during aging. We will use a selective mGluR5 agonist to test whether the stimulation of this receptor can equivalently facilitate memory consolidation in young and aged rats. Retention latency times and MAPK activation will be measured after mGluR5 agonist infusion. Taken together, these results will contribute to the understanding of the role the glutamatergic neurotransmitter systems have in hippocampal synaptic function and aging. This information may also be useful for therapeutic research investigating the potential use of mGluR ligands in age-related neurodegenerative disorders, such as Alzheimer's disease.
| Simonyi, Agnes; Schachtman, Todd R; Christoffersen, Gert R J (2010) Metabotropic glutamate receptor subtype 5 antagonism in learning and memory. Eur J Pharmacol 639:17-25 |
| Simonyi, A; Serfozo, P; Parker, K E et al. (2009) Metabotropic glutamate receptor 5 in conditioned taste aversion learning. Neurobiol Learn Mem 92:460-3 |
| Simonyi, A; Serfozo, P; Shelat, P B et al. (2007) Differential roles of hippocampal metabotropic glutamate receptors 1 and 5 in inhibitory avoidance learning. Neurobiol Learn Mem 88:305-11 |
| Bills, Carla; Schachtman, Todd R; Serfozo, Peter et al. (2005) Effects of metabotropic glutamate receptor 5 on latent inhibition in conditioned taste aversion. Behav Brain Res 157:71-8 |
| Simonyi, Agnes; Schachtman, Todd R; Christoffersen, Gert R J (2005) The role of metabotropic glutamate receptor 5 in learning and memory processes. Drug News Perspect 18:353-61 |
