The metabotropic glutamate receptors (mGluRs) play critical roles in regulating transmission in the hippocampal formation and these actions are important for both acute regulation of hippocampal function and long-lasting forms of synaptic plasticity that may underlie hippocampal-dependent learning and memory. The mGluR5 subtype of mGluR regulates NMDA receptor currents and both long-term potentiation (LTP) and long- term depression (LTD) of transmission in hippocampal area CA1. We have shown that highly selective positive allosteric modulators (PAMs) of mGluR5 enhance both hippocampal LTP and LTD and maintain a strict dependence of both forms of hippocampal synaptic plasticity on specific patterns of activity of presynaptic afferents. This provides an excellent profile for potential cognition-enhancing agents. Exciting progress in developing systemically active mGluR5 PAMs that cross the blood brain barrier makes it possible to rigorously test the hypothesis that selective potentiation of mGluR5 signaling in vivo will enhance hippocampal-dependent forms of learning and memory. In addition to a role of mGluR5 in regulating hippocampal function, we have shown that another group of mGluRs, termed group II mGluRs (mGluR2 and mGluR3), participate in a novel form of glial-neuronal communication in the hippocampus in which activation of mGluRs on astrocytes leads to release of adenosine and reduction of glutamate release from neighboring glutamate synapses. We postulate that this astrocytic response is mediated by the mGluR3 subtype and that activation of mGluR3 could have effects on hippocampal synaptic plasticity that are opposite to those of mGluR5. If so, mGluR3 activation could impair hippocampal LTP and selective antagonists of mGluR3 could have cognition-enhancing effects. We will perform a series of studies to test the hypothesis that mGluR5 PAMs enhance hippocampal-dependent cognitive function and reverse learning deficits in genetically altered mice in which glutamatergic transmission is impaired by selective reductions in expression of the NMDA subtype of glutamate receptor. In addition, we will test the hypothesis that mGluR3 is responsible for this novel form of astrocytic-neuronal communication and that antagonists of mGluR3 can enhance synaptic transmission in the hippocampus and enhance hippocampal-dependent LTP.

Public Health Relevance

A family of neurotransmitter receptors called metabotropic glutamate receptors (mGluRs) have emerged as exciting new drug targets for development of medicines for treatment of a variety of psychiatric and neurological disorders, including Alzheimer's disease, autistic disorders, and schizophrenia. We have discovered new drug like molecules that selectively interact with these receptors. Studies are proposed to determine the effects of these novel molecules in brain circuits that may be critically involved in treatment of these brain disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031373-19
Application #
8444438
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Whittemore, Vicky R
Project Start
1993-08-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
19
Fiscal Year
2013
Total Cost
$322,720
Indirect Cost
$115,848
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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
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