MGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning

Jennifer E. Ayala, Yelin Chen, Jessica L. Banko, Douglas J. Sheffler, Richard Williams, Alexandra N. Telk, Noreen L. Watson, Zixiu Xiang, Yongqin Zhang, Paulianda J. Jones, Craig W. Lindsley, M. Foster Olive, P. Jeffrey Conn

Research output: Contribution to journalArticle

160 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2057-2071
Number of pages15
JournalNeuropsychopharmacology
Volume34
Issue number9
DOIs
StatePublished - Aug 2009

Keywords

  • Allosteric potentiator
  • Group I mGluR
  • LTD
  • LTP
  • MGluR5
  • Synaptic plasticity

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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    Ayala, J. E., Chen, Y., Banko, J. L., Sheffler, D. J., Williams, R., Telk, A. N., Watson, N. L., Xiang, Z., Zhang, Y., Jones, P. J., Lindsley, C. W., Olive, M. F., & Conn, P. J. (2009). MGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning. Neuropsychopharmacology, 34(9), 2057-2071. https://doi.org/10.1038/npp.2009.30