Asynchronous Cholinergic Drive Correlates with Excitation-Inhibition Imbalance via a Neuronal Ca2+ Sensor Protein

Keming Zhou, Salvatore J. Cherra, Alexandr Goncharov, Yishi Jin

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Excitation-inhibition imbalance in neural networks is widely linked to neurological and neuropsychiatric disorders. However, how genetic factors alter neuronal activity, leading to excitation-inhibition imbalance, remains unclear. Here, using the C. elegans locomotor circuit, we examine how altering neuronal activity for varying time periods affects synaptic release pattern and animal behavior. We show that while short-duration activation of excitatory cholinergic neurons elicits a reversible enhancement of presynaptic strength, persistent activation results to asynchronous and reduced cholinergic drive, inducing imbalance between endogenous excitation and inhibition. We find that the neuronal calcium sensor protein NCS-2 is required for asynchronous cholinergic release in an activity-dependent manner and dampens excitability of inhibitory neurons non-cell autonomously. The function of NCS-2 requires its Ca2+ binding and membrane association domains. These results reveal a synaptic mechanism implicating asynchronous release in regulation of excitation-inhibition balance.

Original languageEnglish
Pages (from-to)1117-1129
Number of pages13
JournalCell Reports
Issue number6
StatePublished - May 9 2017

Bibliographical note

Funding Information:
We thank A. Gottschalk, J.S. Dittman, J.-L. Bessereau, H. Bringmann, and J. Rand for strains or reagents; Y.B. Qi for isolating ju836 and ju843; and Z. Wang for Cas9-mediated insertion method. We are grateful to A.D. Chisholm and our lab members for advice and comments. Some strains were provided by the Japan National BioResource Project (NBRP) and the Caenorhabditis Genetics Center (NIH P40 OD010440). This work was supported by NIH grants (R01 NS035546 to Y.J. and F32 NS081945 to S.J.C). K.Z. and A.G. are associates, and Y.J. is an Investigator, of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2017 The Author(s)


  • activity-dependent circuit modification
  • asynchronous release
  • epilepsy
  • excitation-inhibition balance
  • motor circuit
  • presynaptic release kinetics
  • seizure
  • synaptic plasticity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)


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