Deficiency of the 65 kDa Isoform of Glutamic Acid Decarboxylase Impairs Extinction of Cued But Not Contextual Fear Memory

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.

[1]  S. Josselyn,et al.  Increasing CREB in the auditory thalamus enhances memory and generalization of auditory conditioned fear. , 2008, Learning & memory.

[2]  Bernhard Lüscher,et al.  Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues , 1999, Nature Neuroscience.

[3]  Joseph E LeDoux,et al.  Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. , 1992, Behavioral neuroscience.

[4]  D. Paré,et al.  Role of amygdala oscillations in the consolidation of emotional memories , 2004, Biological Psychiatry.

[5]  D. Hanahan,et al.  Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Joseph E LeDoux.  Emotion: clues from the brain. , 1995, Annual review of psychology.

[7]  H. Pape,et al.  Synaptic and non‐synaptic mechanisms of amygdala recruitment into temporolimbic epileptiform activities , 2003, The European journal of neuroscience.

[8]  M. Hasselmo,et al.  GABAergic modulation of hippocampal population activity: sequence learning, place field development, and the phase precession effect. , 1997, Journal of neurophysiology.

[9]  H. Pape,et al.  Neuropeptide S-Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in the Amygdala , 2008, Neuron.

[10]  Joseph E LeDoux.  Emotion circuits in the brain. , 2009, Annual review of neuroscience.

[11]  A. Lüthi,et al.  Switching on and off fear by distinct neuronal circuits , 2008, Nature.

[12]  Y. Yanagawa,et al.  A Specialized Subclass of Interneurons Mediates Dopaminergic Facilitation of Amygdala Function , 2005, Neuron.

[13]  Rajeevan T Narayanan,et al.  Dissociated theta phase synchronization in amygdalo‐ hippocampal circuits during various stages of fear memory , 2007, The European journal of neuroscience.

[14]  D. Paré,et al.  Amygdala intercalated neurons are required for expression of fear extinction , 2008, Nature.

[15]  Michael Davis,et al.  Behavioral and Neural Analysis of Extinction , 2002, Neuron.

[16]  K. Ressler,et al.  Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment , 2004, Neuropsychopharmacology.

[17]  Joseph E LeDoux,et al.  New vistas on amygdala networks in conditioned fear. , 2004, Journal of neurophysiology.

[18]  K. Rimvall,et al.  Regulation of γ‐Aminobutyric Acid Synthesis in the Brain , 1993 .

[19]  S. Baekkeskov,et al.  Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Andreas Lüthi,et al.  Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition , 2006, Nature Neuroscience.

[21]  Hans-Christian Pape,et al.  Amygdalar and Hippocampal Theta Rhythm Synchronization During Fear Memory Retrieval , 2003, Science.

[22]  K. Obata,et al.  Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice , 2003, Genes, brain, and behavior.

[23]  Michael Davis,et al.  Different mechanisms of fear extinction dependent on length of time since fear acquisition. , 2006, Learning & memory.

[24]  T. Yagi,et al.  Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures. , 1996, Biochemical and biophysical research communications.

[25]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[26]  Stephen Maren,et al.  Hippocampal involvement in contextual modulation of fear extinction , 2007, Hippocampus.

[27]  K. Obata,et al.  Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65 , 2000, Brain Research.

[28]  Dawn R. Collins,et al.  Amygdala oscillations and the consolidation of emotional memories , 2002, Trends in Cognitive Sciences.

[29]  B. H. Bland,et al.  Theta band oscillation and synchrony in the hippocampal formation and associated structures: the case for its role in sensorimotor integration , 2001, Behavioural Brain Research.

[30]  H. Pape,et al.  Putative Cortical and Thalamic Inputs Elicit Convergent Excitation in a Population of GABAergic Interneurons of the Lateral Amygdala , 2000, The Journal of Neuroscience.

[31]  D. Paré,et al.  Neuronal Correlates of Fear in the Lateral Amygdala: Multiple Extracellular Recordings in Conscious Cats , 2000, The Journal of Neuroscience.

[32]  Woong Sun,et al.  Amygdala depotentiation and fear extinction , 2007, Proceedings of the National Academy of Sciences.

[33]  Rajeevan T Narayanan,et al.  Theta resynchronization during reconsolidation of remote contextual fear memory , 2007, Neuroreport.

[34]  G. Quirk,et al.  Neural Mechanisms of Extinction Learning and Retrieval , 2008, Neuropsychopharmacology.

[35]  Rajeevan T Narayanan,et al.  Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory. , 2008, Learning & memory.

[36]  H. T. Blair,et al.  Hippocampal Place Cells Acquire Location-Specific Responses to the Conditioned Stimulus during Auditory Fear Conditioning , 2003, Neuron.

[37]  G. Quirk,et al.  Consolidation of Fear Extinction Requires NMDA Receptor-Dependent Bursting in the Ventromedial Prefrontal Cortex , 2007, Neuron.