Deficiency of the 65 kDa isoform of glutamic acid decarboxylase impairs extinction of cued but not contextual fear memory

J Neurosci. 2009 Dec 16;29(50):15713-20. doi: 10.1523/JNEUROSCI.2620-09.2009.


Extinction procedures are clinically relevant for reducing pathological fear, and the mechanisms of fear regulation are a subject of intense research. The amygdala, hippocampus, and prefrontal cortex (PFC) have all been suggested to be key brain areas in extinction of conditioned fear. GABA has particularly been implicated in extinction learning, and the 65 kDa isoform of glutamic acid decarboxylase (GAD65) may be important in elevating GABA levels in response to environmental signals. Extinction of conditioned fear was examined in Gad65(-/-) mice while recording local field potentials from the amygdala, hippocampus, and PFC simultaneously while monitoring behavior. Gad65(-/-) mice showed generalization of cued fear, as reported previously, and impaired extinction of cued fear, such that fear remained high across extinction training. This endurance in cued fear was associated with theta frequency synchronization between the amygdala and hippocampus. Extinction of contextual fear, however, was unaltered in Gad65(-/-) mice when compared with wild-type littermates. The data imply that GAD65 plays a critical role in regulating cued fear responses during extinction learning and that, during this process, GABAergic signaling is involved in modulating synchronized activity between the amygdala and hippocampus. In view of the more pronounced effect on cued versus contextual fear extinction, these influences may rely more on GABAergic mechanisms in the amygdala.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cues*
  • Extinction, Psychological / physiology*
  • Fear / physiology*
  • Fear / psychology
  • Glutamate Decarboxylase / deficiency*
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / physiology
  • Isoenzymes / deficiency
  • Isoenzymes / genetics
  • Isoenzymes / physiology
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout


  • Isoenzymes
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2