Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory.
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.
Bergado-Acosta
Jorge R
JR
Institute for Physiology, Otto-von-Guericke University Magdeburg, D-39120 Magdeburg, Germany.
Sangha
Susan
S
Narayanan
Rajeevan T
RT
Obata
Kunihiko
K
Pape
Hans-Christian
HC
Stork
Oliver
O
D000679:Amygdala / Q000201:enzymology; D000818:Animals; D003214:Conditioning, Classical / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013216:Reflex, Startle / Q000502:physiology
D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2