1. ¹Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
2. ²Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA
3. ³Vanderbilt Institute for Chemical Biology, Vanderbilt University Medical Center, Nashville, TN, USA
4. ⁴Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
5. ⁵Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA
6. ⁶Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA

Correspondence: Dr PJ Conn, Department of Pharmacology, Vanderbilt University Medical Center, 1215D Light Hall, 2215-B Garland Avenue, Nashville, TN 37232-6600, USA. Tel: +1 615 936 2478; Fax: +1 615 343 3088; E-mail: jeffrey.conn@vanderbilt.edu

⁷These authors contributed equally

⁸Current address: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

⁹Current address: College of Medicine Office of Research, University of South Florida, Tampa, FL 33612, USA

Received 7 October 2008; Revised 5 January 2009; Accepted 5 February 2009; Published online 18 March 2009.

Abstract

Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long-term potentiation (LTP) and long-term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on the induction of LTP and LTD at the Schaffer collateral-CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold -burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by the delivery of paired-pulse low-frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD and supports the hypothesis that the activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function.