DevelopmentIntegrative Physiology and BehaviorJournalMotor SystemsNeural Excitability, Synapses, and GliaSensory Systems

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

Circuit function in the CNS relies critically on the balance of excitation and inhibition. In this study, Mende et al. use the mouse spinal reflex circuit to propose a model in which coordinated activity-dependent retrograde signals direct the molecular differentiation of axo-axonically synapsing GABAergic terminals. In this model, the inhibitory potency of GABAergic interneurons is increased in response to excitatory activity, such that a homeostatic balance of excitation and inhibition is maintained. The image depicts a girl on a tightrope, representing the fine balance both required for, and allowed by, functioning proprioceptive reflex circuits. Artwork by Ryuji Yamashita.

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.

Mende et al., Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord, Neuron (2016) 90, 1–14