Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory

  1. Jorge R. Bergado-Acosta1,2,
  2. Susan Sangha3,
  3. Rajeevan T. Narayanan3,
  4. Kunihiko Obata4,
  5. Hans-Christian Pape3, and
  6. Oliver Stork1,2,5,6
  1. 1 Institute for Physiology, Otto-von-Guericke University Magdeburg, D-39120 Magdeburg, Germany;
  2. 2 Department of Molecular Neurobiology, Institute for Biology, Otto-von-Guericke University Magdeburg, D-39120 Magdeburg, Germany;
  3. 3 Institute for Physiology I, Westfälische-Wilhelms-University Münster, D-48149 Münster, Germany;
  4. 4 Neural Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Saitama 351-0198, Japan;
  5. 5 Center for Behavioral Brain Sciences, D-39120 Magdeburg, Germany

Abstract

Evidence suggests that plasticity of the amygdalar and hippocampal GABAergic system is critical for fear memory formation. In this study we investigated in wild-type and genetically manipulated mice the role of the activity-dependent 65-kDa isozyme of glutamic acid decarboxylase (GAD65) in the consolidation and generalization of conditioned fear. First, we demonstrate a transient reduction of GAD65 gene expression in the dorsal hippocampus (6 h post training) and in the basolateral complex of the amygdala (24 h post training) during distinct phases of fear memory consolidation. Second, we show that targeted ablation of the GAD65 gene in Gad65−/− mice results in a pronounced context-independent, intramodal generalization of auditory fear memory during long-term (24 h or 14 d) but not short-term (30 min) memory retrieval. The temporal specificity of both gene regulation and memory deficits in Gad65 mutant mice suggests that GAD65-mediated GABA synthesis is critical for the consolidation of stimulus-specific fear memory. This function appears to involve a modulation of neural activity patterns in the amygdalo-hippocampal pathway as indicated by a reduction in theta frequency synchronization between the amygdala and hippocampus of Gad65−/− mice during the expression of generalized fear memory.

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