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

doi:10.1038/npp.2009.30

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 journal › Article › peer-review

189 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 language	English (US)
Pages (from-to)	2057-2071
Number of pages	15
Journal	Neuropsychopharmacology
Volume	34
Issue number	9
DOIs	https://doi.org/10.1038/npp.2009.30
State	Published - Aug 2009
Externally published	Yes

Keywords

Allosteric potentiator
Group I mGluR
LTD
LTP
MGluR5
Synaptic plasticity

ASJC Scopus subject areas

Pharmacology
Psychiatry and Mental health

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10.1038/npp.2009.30

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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

@article{70db342474d740e5ba9f487cfdbe15fa,

title = "MGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning",

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.",

keywords = "Allosteric potentiator, Group I mGluR, LTD, LTP, MGluR5, Synaptic plasticity",

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

note = "Funding Information: MFO and NLW were supported by PHS grant DA024355. Funding Information: Dr Conn has received compensation over the past 2 years as a consultant from: Merck and Co., Johnson and Johnson, Hoffman La Roche, GlaxoSmithKline, Lundbeck Research USA, Epix Pharmaceuticals, Invitrogen Life Technologies, Evotec Inc., Addex Pharmaceuticals, Michael J Fox Foundation, Seaside Therapeutics, Cephalon Inc., AstraZeneca USA, NeurOp Inc., Forest Research Institute, LEK Consulting, The Frankel Group, Prestwick Chemical Co., Millipore Corp., Genentech, IMS Health, Primary Insight, and Otsuka. He has received honoraria as a speaker from: University of Toronto, American Society for Bone and Mineral Research, University of Alabama Birmingham, University of Michigan, Southern Research Inst., Harvard Medical School, and the University of North Carolina. He receives research support that includes salary support from NIH, Michael J Fox Foundation, Seaside Therapeutics, and Vanderbilt University. Dr Lindsley consults for Amgen and Eisai and receives research support that includes salary support from NIH, Michael J Fox, and Seaside authors have nothing to disclose.",

year = "2009",

month = aug,

doi = "10.1038/npp.2009.30",

language = "English (US)",

volume = "34",

pages = "2057--2071",

journal = "Neuropsychopharmacology",

issn = "0893-133X",

publisher = "Nature Publishing Group",

number = "9",

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TY - JOUR

T1 - MGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning

AU - Ayala, Jennifer E.

AU - Chen, Yelin

AU - Banko, Jessica L.

AU - Sheffler, Douglas J.

AU - Williams, Richard

AU - Telk, Alexandra N.

AU - Watson, Noreen L.

AU - Xiang, Zixiu

AU - Zhang, Yongqin

AU - Jones, Paulianda J.

AU - Lindsley, Craig W.

AU - Olive, M. Foster

AU - Conn, P. Jeffrey

N1 - Funding Information: MFO and NLW were supported by PHS grant DA024355. Funding Information: Dr Conn has received compensation over the past 2 years as a consultant from: Merck and Co., Johnson and Johnson, Hoffman La Roche, GlaxoSmithKline, Lundbeck Research USA, Epix Pharmaceuticals, Invitrogen Life Technologies, Evotec Inc., Addex Pharmaceuticals, Michael J Fox Foundation, Seaside Therapeutics, Cephalon Inc., AstraZeneca USA, NeurOp Inc., Forest Research Institute, LEK Consulting, The Frankel Group, Prestwick Chemical Co., Millipore Corp., Genentech, IMS Health, Primary Insight, and Otsuka. He has received honoraria as a speaker from: University of Toronto, American Society for Bone and Mineral Research, University of Alabama Birmingham, University of Michigan, Southern Research Inst., Harvard Medical School, and the University of North Carolina. He receives research support that includes salary support from NIH, Michael J Fox Foundation, Seaside Therapeutics, and Vanderbilt University. Dr Lindsley consults for Amgen and Eisai and receives research support that includes salary support from NIH, Michael J Fox, and Seaside authors have nothing to disclose.

PY - 2009/8

Y1 - 2009/8

N2 - 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.

AB - 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.

KW - Allosteric potentiator

KW - Group I mGluR

KW - LTD

KW - LTP

KW - MGluR5

KW - Synaptic plasticity

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SN - 0893-133X

VL - 34

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EP - 2071

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

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ER -

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

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