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Neuron. 2018 Sep 5;99(5):941-955.e4. doi: 10.1016/j.neuron.2018.07.026. Epub 2018 Aug 16.

Timing Mechanisms Underlying Gate Control by Feedforward Inhibition.

Author information

1
Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Institute of Acupuncture and Moxibustion, Fudan Institutes of Integrative Medicine, Shanghai 200032, China; Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Fudan University, Shanghai 200032, China; Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu 241002, China.
2
Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Institute of Brain Science, the State Key Laboratory of Medical Neurobiology and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
3
Institute of Brain Science, the State Key Laboratory of Medical Neurobiology and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
4
Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
5
Institute of Acupuncture and Moxibustion, Fudan Institutes of Integrative Medicine, Shanghai 200032, China; Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Fudan University, Shanghai 200032, China; Institute of Brain Science, the State Key Laboratory of Medical Neurobiology and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China. Electronic address: wangyanqing@shmu.edu.cn.
6
Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: qiufu_ma@dfci.harvard.edu.

Abstract

The gate control theory proposes that Aβ mechanoreceptor inputs to spinal pain transmission T neurons are gated via feedforward inhibition, but it remains unclear how monosynaptic excitation is gated by disynaptic inhibitory inputs that arrive later. Here we report that Aβ-evoked, non-NMDAR-dependent EPSPs in T neurons are subthreshold, allowing time for inhibitory inputs to prevent action potential firing that requires slow-onset NMDAR activation. Potassium channel activities-including IA, whose sizes are established constitutively by PreprodynorphinCre-derived inhibitory neurons-either completely filter away Aβ inputs or make them subthreshold, thereby creating a permissive condition to achieve gate control. Capsaicin-activated nociceptor inputs reduce IA and sensitize the T neurons, allowing Aβ inputs to cause firing before inhibitory inputs arrive. Thus, distinct kinetics of glutamate receptors and electric filtering by potassium channels solve the timing problem underlying the gating by feedforward inhibition, and their modulation offers a way to bypass the gate control.

KEYWORDS:

capsaicin; dendritic electric filtering; dynorphin; feedforward inhibition; gate control; glutamate receptors; potassium channels; silent synapses; somatostatin; spinal cord

PMID:
30122375
PMCID:
PMC6309466
DOI:
10.1016/j.neuron.2018.07.026
[Indexed for MEDLINE]
Free PMC Article

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