RGS4 Is Required for Dopaminergic Control of Striatal LTD and Susceptibility to Parkinsonian Motor Deficits

TaliaN Lerner; AnatolC Kreitzer

doi:10.1016/j.neuron.2011.11.015

RGS4 Is Required for Dopaminergic Control of Striatal LTD and Susceptibility to Parkinsonian Motor Deficits

TaliaN Lerner, AnatolC Kreitzer^*

^*Corresponding author for this work

Neuroscience

Research output: Contribution to journal › Article › peer-review

163 Scopus citations

Abstract

Plasticity of excitatory synapses onto striatal projection neurons (MSNs) has the potential to regulate motor function by setting the gain on signals driving both direct- and indirect-pathway basal ganglia circuits. Endocannabinoid-dependent long-term depression (eCB-LTD) is the best characterized form of striatal plasticity, but the mechanisms governing its normal regulation and pathological dysregulation are not well understood. We characterized two distinct signaling pathways mediating eCB production in striatal indirect-pathway MSNs and found that both pathways were modulated by dopamine D2 and adenosine A2A receptors, acting through cAMP/PKA. We identified regulator of G protein signaling 4 (RGS4) as a key link between D2/A2A signaling and eCB mobilization pathways. In contrast to wild-type mice, RGS4 ^-/- mice exhibited normal eCB-LTD after dopamine depletion and were significantly less impaired in the 6-OHDA model of Parkinson's disease. Taken together, these results suggest that inhibition of RGS4 may be aneffective nondopaminergic strategy for treating Parkinson's disease. Video Abstract: Endocannabinoid-dependent LTD is the best characterized form of striatal plasticity, providing potential regulation of basal ganglia function. Lerner and Kreitzer show that regulator of G protein signaling 4 links dopamine D2 and adenosine A2A receptor signaling and endocannabinoid mobilization pathways to regulate plasticity at these synapses.

Original language	English (US)
Pages (from-to)	347-359
Number of pages	13
Journal	Neuron
Volume	73
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2011.11.015
State	Published - Jan 26 2012

Funding

We thank R. Taussig, T. Golde, C. Ceballos, Y. Chen, B. Sabatini, S. Finkbeiner, E. LaDow, E. Korb, L. Shoenfeld, N. Hammack, A. Kravitz, G. Hang, and other members of the Kreitzer Lab for helpful advice on experiments, comments on the manuscript, technical assistance, and reagents. We also thank N. Devidze and B. Masatsugu of the Gladstone Institutes' Behavioral Core for help obtaining the behavioral data. The Gladstone Institutes received support from a National Center for Research Resources grant (RR18928-01). This work was supported by the National Institutes of Health (R01 NS064984), the Pew Biomedical Scholars Program, the W.M. Keck Foundation, and the McKnight Foundation.

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2011.11.015

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title = "RGS4 Is Required for Dopaminergic Control of Striatal LTD and Susceptibility to Parkinsonian Motor Deficits",

abstract = "Plasticity of excitatory synapses onto striatal projection neurons (MSNs) has the potential to regulate motor function by setting the gain on signals driving both direct- and indirect-pathway basal ganglia circuits. Endocannabinoid-dependent long-term depression (eCB-LTD) is the best characterized form of striatal plasticity, but the mechanisms governing its normal regulation and pathological dysregulation are not well understood. We characterized two distinct signaling pathways mediating eCB production in striatal indirect-pathway MSNs and found that both pathways were modulated by dopamine D2 and adenosine A2A receptors, acting through cAMP/PKA. We identified regulator of G protein signaling 4 (RGS4) as a key link between D2/A2A signaling and eCB mobilization pathways. In contrast to wild-type mice, RGS4 -/- mice exhibited normal eCB-LTD after dopamine depletion and were significantly less impaired in the 6-OHDA model of Parkinson's disease. Taken together, these results suggest that inhibition of RGS4 may be aneffective nondopaminergic strategy for treating Parkinson's disease. Video Abstract: Endocannabinoid-dependent LTD is the best characterized form of striatal plasticity, providing potential regulation of basal ganglia function. Lerner and Kreitzer show that regulator of G protein signaling 4 links dopamine D2 and adenosine A2A receptor signaling and endocannabinoid mobilization pathways to regulate plasticity at these synapses.",

author = "TaliaN Lerner and AnatolC Kreitzer",

note = "Funding Information: We thank R. Taussig, T. Golde, C. Ceballos, Y. Chen, B. Sabatini, S. Finkbeiner, E. LaDow, E. Korb, L. Shoenfeld, N. Hammack, A. Kravitz, G. Hang, and other members of the Kreitzer Lab for helpful advice on experiments, comments on the manuscript, technical assistance, and reagents. We also thank N. Devidze and B. Masatsugu of the Gladstone Institutes' Behavioral Core for help obtaining the behavioral data. The Gladstone Institutes received support from a National Center for Research Resources grant (RR18928-01). This work was supported by the National Institutes of Health (R01 NS064984), the Pew Biomedical Scholars Program, the W.M. Keck Foundation, and the McKnight Foundation. ",

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N2 - Plasticity of excitatory synapses onto striatal projection neurons (MSNs) has the potential to regulate motor function by setting the gain on signals driving both direct- and indirect-pathway basal ganglia circuits. Endocannabinoid-dependent long-term depression (eCB-LTD) is the best characterized form of striatal plasticity, but the mechanisms governing its normal regulation and pathological dysregulation are not well understood. We characterized two distinct signaling pathways mediating eCB production in striatal indirect-pathway MSNs and found that both pathways were modulated by dopamine D2 and adenosine A2A receptors, acting through cAMP/PKA. We identified regulator of G protein signaling 4 (RGS4) as a key link between D2/A2A signaling and eCB mobilization pathways. In contrast to wild-type mice, RGS4 -/- mice exhibited normal eCB-LTD after dopamine depletion and were significantly less impaired in the 6-OHDA model of Parkinson's disease. Taken together, these results suggest that inhibition of RGS4 may be aneffective nondopaminergic strategy for treating Parkinson's disease. Video Abstract: Endocannabinoid-dependent LTD is the best characterized form of striatal plasticity, providing potential regulation of basal ganglia function. Lerner and Kreitzer show that regulator of G protein signaling 4 links dopamine D2 and adenosine A2A receptor signaling and endocannabinoid mobilization pathways to regulate plasticity at these synapses.

AB - Plasticity of excitatory synapses onto striatal projection neurons (MSNs) has the potential to regulate motor function by setting the gain on signals driving both direct- and indirect-pathway basal ganglia circuits. Endocannabinoid-dependent long-term depression (eCB-LTD) is the best characterized form of striatal plasticity, but the mechanisms governing its normal regulation and pathological dysregulation are not well understood. We characterized two distinct signaling pathways mediating eCB production in striatal indirect-pathway MSNs and found that both pathways were modulated by dopamine D2 and adenosine A2A receptors, acting through cAMP/PKA. We identified regulator of G protein signaling 4 (RGS4) as a key link between D2/A2A signaling and eCB mobilization pathways. In contrast to wild-type mice, RGS4 -/- mice exhibited normal eCB-LTD after dopamine depletion and were significantly less impaired in the 6-OHDA model of Parkinson's disease. Taken together, these results suggest that inhibition of RGS4 may be aneffective nondopaminergic strategy for treating Parkinson's disease. Video Abstract: Endocannabinoid-dependent LTD is the best characterized form of striatal plasticity, providing potential regulation of basal ganglia function. Lerner and Kreitzer show that regulator of G protein signaling 4 links dopamine D2 and adenosine A2A receptor signaling and endocannabinoid mobilization pathways to regulate plasticity at these synapses.

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ER -

RGS4 Is Required for Dopaminergic Control of Striatal LTD and Susceptibility to Parkinsonian Motor Deficits

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