Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord

Michael Mende; Emily V. Fletcher; Josephine L. Belluardo; Joseph P. Pierce; Praveen K. Bommareddy; Jarret A. Weinrich; Zeeba D. Kabir; Kathryn C. Schierberl; John G. Pagiazitis; Alana I. Mendelsohn; Anna Francesconi; Robert H. Edwards; Teresa A. Milner; Anjali M. Rajadhyaksha; Peter J. van Roessel; George Z. Mentis; Julia A. Kaltschmidt

doi:10.1016/j.neuron.2016.05.008

Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord

Michael Mende, Emily V. Fletcher, Josephine L. Belluardo, Joseph P. Pierce, Praveen K. Bommareddy, Jarret A. Weinrich, Zeeba D. Kabir, Kathryn C. Schierberl, John G. Pagiazitis, Alana I. Mendelsohn, Anna Francesconi, Robert H. Edwards, Teresa A. Milner, Anjali M. Rajadhyaksha, Peter J. van Roessel, George Z. Mentis, Julia A. Kaltschmidt

Neuroscience

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Abstract

Circuit function in the CNS relies on the balanced interplay of excitatory and inhibitory synaptic signaling. How neuronal activity influences synaptic differentiation to maintain such balance remains unclear. In the mouse spinal cord, a population of GABAergic interneurons, GABApre, forms synapses with the terminals of proprioceptive sensory neurons and controls information transfer at sensory-motor connections through presynaptic inhibition. We show that reducing sensory glutamate release results in decreased expression of GABA-synthesizing enzymes GAD65 and GAD67 in GABApre terminals and decreased presynaptic inhibition. Glutamate directs GAD67 expression via the metabotropic glutamate receptor mGluR1β on GABApre terminals and regulates GAD65 expression via autocrine influence on sensory terminal BDNF. We demonstrate that dual retrograde signals from sensory terminals operate hierarchically to direct the molecular differentiation of GABApre terminals and the efficacy of presynaptic inhibition. These retrograde signals comprise a feedback mechanism by which excitatory sensory activity drives GABAergic inhibition to maintain circuit homeostasis.

Original language	English (US)
Pages (from-to)	1189-1202
Number of pages	14
Journal	Neuron
Volume	90
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2016.05.008
State	Published - Jun 15 2016

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10.1016/j.neuron.2016.05.008

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Mende, M., Fletcher, E. V., Belluardo, J. L., Pierce, J. P., Bommareddy, P. K., Weinrich, J. A., Kabir, Z. D., Schierberl, K. C., Pagiazitis, J. G., Mendelsohn, A. I., Francesconi, A., Edwards, R. H., Milner, T. A., Rajadhyaksha, A. M., van Roessel, P. J., Mentis, G. Z., & Kaltschmidt, J. A. (2016). Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord. Neuron, 90(6), 1189-1202. https://doi.org/10.1016/j.neuron.2016.05.008

Mende, M, Fletcher, EV, Belluardo, JL, Pierce, JP, Bommareddy, PK, Weinrich, JA, Kabir, ZD, Schierberl, KC, Pagiazitis, JG, Mendelsohn, AI, Francesconi, A, Edwards, RH, Milner, TA, Rajadhyaksha, AM, van Roessel, PJ, Mentis, GZ & Kaltschmidt, JA 2016, 'Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord', Neuron, vol. 90, no. 6, pp. 1189-1202. https://doi.org/10.1016/j.neuron.2016.05.008

@article{f10cca54fafc49a783854ab8c83849dd,

title = "Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord",

abstract = "Circuit function in the CNS relies on the balanced interplay of excitatory and inhibitory synaptic signaling. How neuronal activity influences synaptic differentiation to maintain such balance remains unclear. In the mouse spinal cord, a population of GABAergic interneurons, GABApre, forms synapses with the terminals of proprioceptive sensory neurons and controls information transfer at sensory-motor connections through presynaptic inhibition. We show that reducing sensory glutamate release results in decreased expression of GABA-synthesizing enzymes GAD65 and GAD67 in GABApre terminals and decreased presynaptic inhibition. Glutamate directs GAD67 expression via the metabotropic glutamate receptor mGluR1β on GABApre terminals and regulates GAD65 expression via autocrine influence on sensory terminal BDNF. We demonstrate that dual retrograde signals from sensory terminals operate hierarchically to direct the molecular differentiation of GABApre terminals and the efficacy of presynaptic inhibition. These retrograde signals comprise a feedback mechanism by which excitatory sensory activity drives GABAergic inhibition to maintain circuit homeostasis.",

author = "Michael Mende and Fletcher, {Emily V.} and Belluardo, {Josephine L.} and Pierce, {Joseph P.} and Bommareddy, {Praveen K.} and Weinrich, {Jarret A.} and Kabir, {Zeeba D.} and Schierberl, {Kathryn C.} and Pagiazitis, {John G.} and Mendelsohn, {Alana I.} and Anna Francesconi and Edwards, {Robert H.} and Milner, {Teresa A.} and Rajadhyaksha, {Anjali M.} and {van Roessel}, {Peter J.} and Mentis, {George Z.} and Kaltschmidt, {Julia A.}",

note = "Funding Information: We are grateful to Drs. Francisco Alvarez, Nicholas Betley, Thomas Jessell, Anna Kalinovsky, and Michael O{\textquoteright}Donovan and members of the Mentis and Kaltschmidt labs for helpful discussions and comments on the manuscript. We thank Jeffrey Russ for critical assistance with in situ hybridization; Richard DiCasoli, Kim Kridsada, and Sarah Qamar for technical assistance; Thomas Jessell, Susan Morton, and Ryuichi Shigemoto for providing antibodies; Miranda Karson and Bradley Alger for mGluR1::LacZ mice; and Lily Erdy and Kirsten Hively for help with preparing the manuscript. This work was supported by NIH grants DA08259 , HL096571 , and HL098351 (T.A.M.); NIH grants T32 DA007274 (K.C.S.) and 5R01DA029122 (A.M.R.); by NIH grant MH082870 and a Brain & Behavior Research Foundation NARSAD award (A.F.); by NIH grant 5R01-NS078375-01 , an Audrey Lewis Young Investigator award from Families of SMA , and a Department of Defense ( 10235006 ) grant (G.Z.M.); and by NIH grants 2 T32 HD 60600-6 (J.L.B.) and 5R01-NS083998 , Memorial Sloan-Kettering start-up funds, MSK Cancer Center Support Grant/Core Grant ( P30 CA008748 ), a Whitehall Foundation Research Grant and a Louis V. Gerstner, Jr. Young Investigators Award (J.A.K.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = jun,

day = "15",

doi = "10.1016/j.neuron.2016.05.008",

language = "English (US)",

volume = "90",

pages = "1189--1202",

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T1 - Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord

AU - Mende, Michael

AU - Fletcher, Emily V.

AU - Belluardo, Josephine L.

AU - Pierce, Joseph P.

AU - Bommareddy, Praveen K.

AU - Weinrich, Jarret A.

AU - Kabir, Zeeba D.

AU - Schierberl, Kathryn C.

AU - Pagiazitis, John G.

AU - Mendelsohn, Alana I.

AU - Francesconi, Anna

AU - Edwards, Robert H.

AU - Milner, Teresa A.

AU - Rajadhyaksha, Anjali M.

AU - van Roessel, Peter J.

AU - Mentis, George Z.

AU - Kaltschmidt, Julia A.

N1 - Funding Information: We are grateful to Drs. Francisco Alvarez, Nicholas Betley, Thomas Jessell, Anna Kalinovsky, and Michael O’Donovan and members of the Mentis and Kaltschmidt labs for helpful discussions and comments on the manuscript. We thank Jeffrey Russ for critical assistance with in situ hybridization; Richard DiCasoli, Kim Kridsada, and Sarah Qamar for technical assistance; Thomas Jessell, Susan Morton, and Ryuichi Shigemoto for providing antibodies; Miranda Karson and Bradley Alger for mGluR1::LacZ mice; and Lily Erdy and Kirsten Hively for help with preparing the manuscript. This work was supported by NIH grants DA08259 , HL096571 , and HL098351 (T.A.M.); NIH grants T32 DA007274 (K.C.S.) and 5R01DA029122 (A.M.R.); by NIH grant MH082870 and a Brain & Behavior Research Foundation NARSAD award (A.F.); by NIH grant 5R01-NS078375-01 , an Audrey Lewis Young Investigator award from Families of SMA , and a Department of Defense ( 10235006 ) grant (G.Z.M.); and by NIH grants 2 T32 HD 60600-6 (J.L.B.) and 5R01-NS083998 , Memorial Sloan-Kettering start-up funds, MSK Cancer Center Support Grant/Core Grant ( P30 CA008748 ), a Whitehall Foundation Research Grant and a Louis V. Gerstner, Jr. Young Investigators Award (J.A.K.). Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/6/15

Y1 - 2016/6/15

N2 - Circuit function in the CNS relies on the balanced interplay of excitatory and inhibitory synaptic signaling. How neuronal activity influences synaptic differentiation to maintain such balance remains unclear. In the mouse spinal cord, a population of GABAergic interneurons, GABApre, forms synapses with the terminals of proprioceptive sensory neurons and controls information transfer at sensory-motor connections through presynaptic inhibition. We show that reducing sensory glutamate release results in decreased expression of GABA-synthesizing enzymes GAD65 and GAD67 in GABApre terminals and decreased presynaptic inhibition. Glutamate directs GAD67 expression via the metabotropic glutamate receptor mGluR1β on GABApre terminals and regulates GAD65 expression via autocrine influence on sensory terminal BDNF. We demonstrate that dual retrograde signals from sensory terminals operate hierarchically to direct the molecular differentiation of GABApre terminals and the efficacy of presynaptic inhibition. These retrograde signals comprise a feedback mechanism by which excitatory sensory activity drives GABAergic inhibition to maintain circuit homeostasis.

AB - Circuit function in the CNS relies on the balanced interplay of excitatory and inhibitory synaptic signaling. How neuronal activity influences synaptic differentiation to maintain such balance remains unclear. In the mouse spinal cord, a population of GABAergic interneurons, GABApre, forms synapses with the terminals of proprioceptive sensory neurons and controls information transfer at sensory-motor connections through presynaptic inhibition. We show that reducing sensory glutamate release results in decreased expression of GABA-synthesizing enzymes GAD65 and GAD67 in GABApre terminals and decreased presynaptic inhibition. Glutamate directs GAD67 expression via the metabotropic glutamate receptor mGluR1β on GABApre terminals and regulates GAD65 expression via autocrine influence on sensory terminal BDNF. We demonstrate that dual retrograde signals from sensory terminals operate hierarchically to direct the molecular differentiation of GABApre terminals and the efficacy of presynaptic inhibition. These retrograde signals comprise a feedback mechanism by which excitatory sensory activity drives GABAergic inhibition to maintain circuit homeostasis.

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JO - Neuron

JF - Neuron

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ER -

Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord

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