TY  - JOUR
AU  - Lange, Maren D
AU  - Jüngling, Kay
AU  - Paulukat, Linda
AU  - Vieler, Marc
AU  - Gaburro, Stefano
AU  - Sosulina, Liudmila
AU  - Blaesse, Peter
AU  - Sreepathi, Hari K
AU  - Ferraguti, Francesco
AU  - Pape, Hans-Christian
TI  - Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization.
JO  - Neuropsychopharmacology
VL  - 39
IS  - 9
SN  - 0893-133X
CY  - Basingstoke
PB  - Nature Publishing Group71819
M1  - DZNE-2020-07625
SP  - 2211-2220
PY  - 2014
AB  - 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.
KW  - Amygdala: cytology
KW  - Amygdala: enzymology
KW  - Animals
KW  - Association Learning: physiology
KW  - Conditioning, Psychological: physiology
KW  - Electroshock
KW  - Extracellular Space: metabolism
KW  - Fear: physiology
KW  - Generalization, Psychological: physiology
KW  - Glutamate Decarboxylase: genetics
KW  - Glutamate Decarboxylase: metabolism
KW  - Glutamic Acid: metabolism
KW  - Interneurons: cytology
KW  - Interneurons: physiology
KW  - Long-Term Potentiation: physiology
KW  - Male
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Neurons: cytology
KW  - Neurons: physiology
KW  - Receptors, GABA-B: metabolism
KW  - Synaptic Transmission: physiology
KW  - gamma-Aminobutyric Acid: metabolism
KW  - Receptors, GABA-B (NLM Chemicals)
KW  - Glutamic Acid (NLM Chemicals)
KW  - gamma-Aminobutyric Acid (NLM Chemicals)
KW  - Glutamate Decarboxylase (NLM Chemicals)
KW  - glutamate decarboxylase 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24663011
C2  - pmc:PMC4104340
DO  - DOI:10.1038/npp.2014.72
UR  - https://pub.dzne.de/record/141303
ER  -