The hippocampus plays an important role in a number of normal physiological processes and in pathological conditions, including Alzheimer's disease and epilepsy. Development of a complete understanding of the molecular and cellular mechanisms of regulation of synaptic function in the hippocampus could lead to new strategies for treatment of these disorders. Until recently, it was thought that all of the actions of glutamate, the major excitatory neurotransmitter in the hippocampus, were mediated by activation of ligand-gated cation channels. However, it is now clear that glutamate also activates metabotropic glutamate receptors (mGluRs), that are coupled to effector systems through GTP binding proteins. mGluRs play a number of important roles in regulating cell excitability and synaptic transmission in the hippocampus. However, the precise physiological roles of the different mGluR subtypes are not known. A complete understanding of both normal and pathological hippocampal function will require a detailed understanding of the roles of mGluRs in regulating hippocampal physiology. Eight mGluR subtypes have been cloned and these receptors have been classified into three major groups. Many of the physiolological roles of group I mGluRs (mGluR1 and mGluR5) in the hippocampus have been defined, but less is known about the physiological roles of the group II (mGluR2 and mGluR3) and group III (mGluRs 4, 6, 7, and 8) mGluRs. A series of studies is proposed that is aimed at determining the localization and physiological roles of group II and group III mGluRs in the hippocampus and the cellular mechanisms by which activation of these receptors modulates hippocampal function. Patch clamp recordings in hippocampal slices and studies of mGluR pharmacology in expression systems will be used to test the hypothesis that a group II mGluR serves as an autoreceptor at the perforant path synapses. mGluR2 and mGluR3-specific antibodies will then be used for immunocytochemistry with electron microscopy (immuno-EM) to definitively determine whether mGluR2 and/or mGluR3 is presynaptically localized at these synapses. Immuno-EM will then be used to test the hypothesis that mGluR4a is localized postsynaptically and mGluR7 presynaptically on hippocampal neurons. Patch clamp recordings in hippocampal slices and studies of mGluR4a and mGluR7 pharmacology in expression systems will then be used to test the hypothesis that these receptors play distinct pre- and postsynaptic roles in the hippocampus. In addition to advancing our knowledge of hippocampal function, these studies will lead to a more complete understanding of the physiology and pharmacology of the mGluR family. Glutamate is the major excitatory neurotransmitter in the central nervous system and glutamatergic synapses are widespread throughout the brain. Thus, the mGluRs are likely to play important roles in various aspects of brain function. Developing an understanding of the physiological roles of each mGluR subtype will ultimately lead to advances in a number of areas of neurobiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031373-06
Application #
2750863
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Baughman, Robert W
Project Start
1993-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Doria, Juliana G; de Souza, Jessica M; Silva, Flavia R et al. (2018) The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease. J Neurochem 147:222-239
Yohn, Samantha E; Conn, P Jeffrey (2018) Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia. Neuropharmacology 136:438-448
Stansley, Branden J; Conn, P Jeffrey (2018) The therapeutic potential of metabotropic glutamate receptor modulation for schizophrenia. Curr Opin Pharmacol 38:31-36
Joffe, Max E; Centanni, Samuel W; Jaramillo, Anel A et al. (2018) Metabotropic Glutamate Receptors in Alcohol Use Disorder: Physiology, Plasticity, and Promising Pharmacotherapies. ACS Chem Neurosci 9:2188-2204
Gogliotti, Rocco G; Senter, Rebecca K; Fisher, Nicole M et al. (2017) mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. Sci Transl Med 9:
Moehle, Mark S; Pancani, Tristano; Byun, Nellie et al. (2017) Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M4 Muscarinic Receptor. Neuron 96:1358-1372.e4
Walker, Adam G; Sheffler, Douglas J; Lewis, Andrew S et al. (2017) Co-Activation of Metabotropic Glutamate Receptor 3 and Beta-Adrenergic Receptors Modulates Cyclic-AMP and Long-Term Potentiation, and Disrupts Memory Reconsolidation. Neuropsychopharmacology 42:2553-2566
Gogliotti, Rocco G; Senter, Rebecca K; Rook, Jerri M et al. (2016) mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome. Hum Mol Genet 25:1990-2004
Niswender, Colleen M; Jones, Carrie K; Lin, Xin et al. (2016) Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers. ACS Chem Neurosci 7:1201-11
Senter, Rebecca K; Ghoshal, Ayan; Walker, Adam G et al. (2016) The Role of mGlu Receptors in Hippocampal Plasticity Deficits in Neurological and Psychiatric Disorders: Implications for Allosteric Modulators as Novel Therapeutic Strategies. Curr Neuropharmacol 14:455-73

Showing the most recent 10 out of 132 publications