TY - JOUR
T1 - Co-activation of metabotropic glutamate receptor 3 and beta-adrenergic receptors modulates cyclic-AMP and long-term potentiation, and disrupts memory reconsolidation
AU - Walker, Adam G.
AU - Sheffler, Douglas J.
AU - Lewis, Andrew S.
AU - Dickerson, Jonathan W.
AU - Foster, Daniel J.
AU - Senter, Rebecca K.
AU - Moehle, Mark S.
AU - Lv, Xiaohui
AU - Stansley, Branden J.
AU - Xiang, Zixiu
AU - Rook, Jerri M.
AU - Emmitte, Kyle A.
AU - Lindsley, Craig W.
AU - Conn, P. Jeffrey
N1 - Funding Information:
This work was supported by a National Institute of Neurological Disorders and Stroke (NINDS) grant R01-NS031373 (to PJC). DJS was a recipient of a National Alliance for Research on Schizophrenia and Depression (NARSAD), Dylan Tauber Young Investigator Award. AGW was supported by a postdoctoral fellowship through the PhRMA Foundation. Immunohistochemical experiments were performed in part through the use of the Vanderbilt Cell Imagining Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, DK59637, and EY08126). Drs Emmitte, Lindsley, and Conn are inventors on patents protecting different classes of mGlu2 and mGlu3 modulators. Dr Emmitte’s work has been funded by the NIH. Dr Lindsley's work has been funded by the NIH, Bristol-Myers Squibb, AstraZeneca, Michael J Fox Foundation, as well as Seaside Therapeutics. He has consulted for AbbVie and received compensation. Dr Conn has been funded by NIH, Johnson & Johnson, AstraZeneca, Bristol-Myers Squibb, Michael J Fox Foundation, and Seaside Therapeutics. Over the past 3 years, he has served on the Scientific Advisory Boards of Seaside Therapeutics, Michael J Fox Foundation, Stanley Center for Psychiatric Research Broad Institute (MIT/Harvard), Karuna Pharmaceuticals, Lieber Institute for Brain Development Johns Hopkins University, Clinical Mechanism (POCM) and Proof of Concept (POC) Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder. The authors declare no conflicts of interest.
Publisher Copyright:
© 2017 American College of Neuropsychopharmacology. All rights reserved.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Activation of β-adrenergic receptors (βARs) enhances both the induction of long-term potentiation (LTP) in hippocampal CA1 pyramidal cells and hippocampal-dependent cognitive function. Interestingly, previous studies reveal that coincident activation of group II metabotropic glutamate (mGlu) receptors with βARs in the hippocampal astrocytes induces a large increase in cyclic-AMP (cAMP) accumulation and release of adenosine. Adenosine then acts on A 1 adenosine receptors at neighboring excitatory Schaffer collateral terminals, which could counteract effects of activation of neuronal βARs on excitatory transmission. On the basis of this, we postulated that activation of the specific mGlu receptor subtype that mediates this response could inhibit βAR-mediated effects on hippocampal synaptic plasticity and cognitive function. Using novel mGlu receptor subtype-selective allosteric modulators along with knockout mice we now report that the effects of mGlu 2/3 agonists on βAR-mediated increases in cAMP accumulation are exclusively mediated by mGlu 3. Furthermore, mGlu 3 activation inhibits the ability of the βAR agonist isoproterenol to enhance hippocampal LTP, and this effect is absent in slices treated with either a glial toxin or an adenosine A 1 receptor antagonist. Finally, systemic administration of the mGlu 2/3 agonist LY379268 disrupted contextual fear memory in a manner similar to the effect of the βAR antagonist propranolol, and this effect was reversed by the mGlu 3 -negative allosteric modulator VU0650786. Taken together, these data suggest that mGlu 3 can influence astrocytic signaling and modulate βAR-mediated effects on hippocampal synaptic plasticity and cognitive function.
AB - Activation of β-adrenergic receptors (βARs) enhances both the induction of long-term potentiation (LTP) in hippocampal CA1 pyramidal cells and hippocampal-dependent cognitive function. Interestingly, previous studies reveal that coincident activation of group II metabotropic glutamate (mGlu) receptors with βARs in the hippocampal astrocytes induces a large increase in cyclic-AMP (cAMP) accumulation and release of adenosine. Adenosine then acts on A 1 adenosine receptors at neighboring excitatory Schaffer collateral terminals, which could counteract effects of activation of neuronal βARs on excitatory transmission. On the basis of this, we postulated that activation of the specific mGlu receptor subtype that mediates this response could inhibit βAR-mediated effects on hippocampal synaptic plasticity and cognitive function. Using novel mGlu receptor subtype-selective allosteric modulators along with knockout mice we now report that the effects of mGlu 2/3 agonists on βAR-mediated increases in cAMP accumulation are exclusively mediated by mGlu 3. Furthermore, mGlu 3 activation inhibits the ability of the βAR agonist isoproterenol to enhance hippocampal LTP, and this effect is absent in slices treated with either a glial toxin or an adenosine A 1 receptor antagonist. Finally, systemic administration of the mGlu 2/3 agonist LY379268 disrupted contextual fear memory in a manner similar to the effect of the βAR antagonist propranolol, and this effect was reversed by the mGlu 3 -negative allosteric modulator VU0650786. Taken together, these data suggest that mGlu 3 can influence astrocytic signaling and modulate βAR-mediated effects on hippocampal synaptic plasticity and cognitive function.
UR - http://www.scopus.com/inward/record.url?scp=85033560644&partnerID=8YFLogxK
U2 - 10.1038/npp.2017.136
DO - 10.1038/npp.2017.136
M3 - Article
C2 - 28664928
AN - SCOPUS:85033560644
SN - 0893-133X
VL - 42
SP - 2553
EP - 2566
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 13
ER -