Co-activation of metabotropic glutamate receptor 3 and beta-adrenergic receptors modulates cyclic-AMP and long-term potentiation, and disrupts memory reconsolidation

Adam G. Walker, Douglas J. Sheffler, Andrew S. Lewis, Jonathan W. Dickerson, Daniel J. Foster, Rebecca K. Senter, Mark S. Moehle, Xiaohui Lv, Branden J. Stansley, Zixiu Xiang, Jerri M. Rook, Kyle Allen Emmitte, Craig W. Lindsley, P. Jeffrey Conn

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Abstract

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.

Original languageEnglish
Pages (from-to)2553-2566
Number of pages14
JournalNeuropsychopharmacology
Volume42
Issue number13
DOIs
StatePublished - 1 Dec 2017

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Long-Term Potentiation
Receptors, Adrenergic, beta
Cyclic AMP
Glutamic Acid
Adrenergic Receptors
Metabotropic Glutamate Receptors
Adenosine
Cognition
Adrenergic Agonists
Neuronal Plasticity
LY 379268
Purinergic P1 Receptors
Adrenergic Antagonists
Aptitude
Pyramidal Cells
Isoproterenol
Knockout Mice
Propranolol
Neuroglia
Astrocytes

Cite this

Walker, Adam G. ; Sheffler, Douglas J. ; Lewis, Andrew S. ; Dickerson, Jonathan W. ; Foster, Daniel J. ; Senter, Rebecca K. ; Moehle, Mark S. ; Lv, Xiaohui ; Stansley, Branden J. ; Xiang, Zixiu ; Rook, Jerri M. ; Emmitte, Kyle Allen ; Lindsley, Craig W. ; Conn, P. Jeffrey. / Co-activation of metabotropic glutamate receptor 3 and beta-adrenergic receptors modulates cyclic-AMP and long-term potentiation, and disrupts memory reconsolidation. In: Neuropsychopharmacology. 2017 ; Vol. 42, No. 13. pp. 2553-2566.
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title = "Co-activation of metabotropic glutamate receptor 3 and beta-adrenergic receptors modulates cyclic-AMP and long-term potentiation, and disrupts memory reconsolidation",
abstract = "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.",
author = "Walker, {Adam G.} and Sheffler, {Douglas J.} and Lewis, {Andrew S.} and Dickerson, {Jonathan W.} and Foster, {Daniel J.} and Senter, {Rebecca K.} and Moehle, {Mark S.} and Xiaohui Lv and Stansley, {Branden J.} and Zixiu Xiang and Rook, {Jerri M.} and Emmitte, {Kyle Allen} and Lindsley, {Craig W.} and Conn, {P. Jeffrey}",
year = "2017",
month = "12",
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doi = "10.1038/npp.2017.136",
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Walker, AG, Sheffler, DJ, Lewis, AS, Dickerson, JW, Foster, DJ, Senter, RK, Moehle, MS, Lv, X, Stansley, BJ, Xiang, Z, Rook, JM, Emmitte, KA, Lindsley, CW & Conn, PJ 2017, 'Co-activation of metabotropic glutamate receptor 3 and beta-adrenergic receptors modulates cyclic-AMP and long-term potentiation, and disrupts memory reconsolidation', Neuropsychopharmacology, vol. 42, no. 13, pp. 2553-2566. https://doi.org/10.1038/npp.2017.136

Co-activation of metabotropic glutamate receptor 3 and beta-adrenergic receptors modulates cyclic-AMP and long-term potentiation, and disrupts memory reconsolidation. / Walker, Adam G.; Sheffler, Douglas J.; Lewis, Andrew S.; Dickerson, Jonathan W.; Foster, Daniel J.; Senter, Rebecca K.; Moehle, Mark S.; Lv, Xiaohui; Stansley, Branden J.; Xiang, Zixiu; Rook, Jerri M.; Emmitte, Kyle Allen; Lindsley, Craig W.; Conn, P. Jeffrey.

In: Neuropsychopharmacology, Vol. 42, No. 13, 01.12.2017, p. 2553-2566.

Research output: Contribution to journalArticleResearchpeer-review

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 Allen

AU - Lindsley, Craig W.

AU - Conn, P. Jeffrey

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.

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