Dentate Gyrus Local Circuit is Implicated in Learning Under Stress--a Role for Neurofascin

Mol Neurobiol. 2016 Mar;53(2):842-850. doi: 10.1007/s12035-014-9044-7. Epub 2014 Dec 17.


The inhibitory synapses at the axon initial segment (AIS) of dentate gyrus granular cells are almost exclusively innervated by the axo-axonic chandelier interneurons. However, the role of chandelier neurons in local circuitry is poorly understood and controversially discussed. The cell adhesion molecule neurofascin is specifically expressed at the AIS. It is crucially required for the stabilization of axo-axonic synapses. Knockdown of neurofascin is therefore a convenient tool to interfere with chandelier input at the AIS of granular neurons of the dentate gyrus. In the current study, feedback and feedforward inhibition of granule cells was measured in the dentate gyrus after knockdown of neurofascin and concomitant reduction of axo-axonic input. Results show increased feedback inhibition as a result of neurofascin knockdown, while feedforward inhibition remained unaffected. This suggests that chandelier neurons are predominantly involved in feedback inhibition. Neurofascin knockdown rats also exhibited impaired learning under stress in the two-way shuttle avoidance task. Remarkably, this learning impairment was not accompanied by differences in electrophysiological measurements of dentate gyrus LTP. This indicates that the local circuit may be involved in (certain types) of learning.

Keywords: Axon initial segment (AIS); GABAA receptor clustering; Hippocampus; Learning impairment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning
  • Axons / metabolism
  • Behavior, Animal
  • Cell Adhesion Molecules / metabolism*
  • Dentate Gyrus / metabolism*
  • Electric Stimulation
  • GABAergic Neurons / metabolism
  • Gene Knockdown Techniques
  • Learning*
  • Long-Term Potentiation
  • Male
  • Nerve Growth Factors / metabolism*
  • Neural Pathways / metabolism*
  • Rats, Sprague-Dawley
  • Stress, Psychological / metabolism*


  • Cell Adhesion Molecules
  • Nerve Growth Factors
  • Nfasc protein, rat