Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization

Neuropsychopharmacology. 2014 Aug;39(9):2211-20. doi: 10.1038/npp.2014.72. Epub 2014 Mar 25.


An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / cytology
  • Amygdala / enzymology*
  • Animals
  • Association Learning / physiology
  • Conditioning, Psychological / physiology
  • Electroshock
  • Extracellular Space / metabolism
  • Fear / physiology*
  • Generalization, Psychological / physiology*
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism*
  • Glutamic Acid / metabolism
  • Interneurons / cytology
  • Interneurons / physiology
  • Long-Term Potentiation / physiology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / physiology
  • Receptors, GABA-B / metabolism
  • Synaptic Transmission / physiology*
  • gamma-Aminobutyric Acid / metabolism*


  • Receptors, GABA-B
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2