Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord.
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.
Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.
Michael
M
Mende
Department of Pathology and Cell Biology and Department of Neurology, Columbia University, New York, NY 10032, USA; Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Emily V
EV
Fletcher
Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA; Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA.
Josephine L
JL
Belluardo
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
Joseph P
JP
Pierce
Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.
Praveen K
PK
Bommareddy
Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA; Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA.
Jarret A
JA
Weinrich
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY 10065, USA.
Zeeba D
ZD
Kabir
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY 10065, USA.
Kathryn C
KC
Schierberl
Department of Pathology and Cell Biology and Department of Neurology, Columbia University, New York, NY 10032, USA; Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
John G
JG
Pagiazitis
Howard Hughes Medical Institute, Kavli Institute for Brain Science, Zuckerman Mind Brain Behavior Institute, Department of Neuroscience and Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
Alana I
AI
Mendelsohn
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Anna
A
Francesconi
Department of Neurology and Department of Physiology, Graduate Programs in Neuroscience and Cell Biology, UCSF School of Medicine, San Francisco, CA 94143, USA.
Robert H
RH
Edwards
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA.
Teresa A
TA
Milner
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY 10065, USA.
Anjali M
AM
Rajadhyaksha
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Peter J
PJ
van Roessel
Department of Pathology and Cell Biology and Department of Neurology, Columbia University, New York, NY 10032, USA; Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA. Electronic address: gzmentis@columbia.edu.
George Z
GZ
Mentis
Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA; Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA; Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: kaltschj@mskcc.org.
Julia A
JA
Kaltschmidt
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology*; D007395:Interneurons / Q000502:physiology; D051379:Mice; D008959:Models, Neurological; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D017729:Presynaptic Terminals / Q000378:metabolism / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
D019208:Brain-Derived Neurotrophic Factor; D018094:Receptors, Metabotropic Glutamate; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2