GABA and Fear
Extinction is a complex phenomenon but generally is regarded as a new inhibitory learning that suppresses the original memory. However, how or from where the inhibition originates remains to be determined. In the present study, we examine whether increase in the expression of γ-aminobutyric acid (GABA)A receptors in the amygdala is required for extinction by employing cell-permeable TAT-conjugated peptide (TAT)-GABA receptor-associated protein (GABARAP) inhibitory peptide to block GABAA receptor insertion.
Retention of fear memory was assessed with fear-potentiated startle paradigm. Whole cell patch clamp recordings were performed to record miniature inhibitory postsynaptic current (mIPSC). Western blotting analysis was used to measure the expression of gephyrin, β2, and γ2 subunits of GABAA receptor.
Fear conditioning decreased frequency and amplitude of mIPSC and surface protein levels of β2 and γ2 subunits of GABAA receptor. Extinction training, by contrast, reversed the decreased frequency and amplitude of mIPSC and surface protein levels of gephyrin and β2 subunit of GABAA receptor. Disruption of GABARAP-GABAA receptor interaction in the amygdala with GABARAP inhibitory peptide blocked N-methyl-D-aspartate–mediated GABAA receptor insertion in the amygdala. Importantly, it also blocked extinction-induced increase in the frequency and amplitude of mIPSCs, and the reduction of fear-potentiated startle.
GABAA receptor insertion in the amygdala contributes a significant part to the extinction of fear memory.
From press release:
There are increasingly precise molecular insights into ways that stress exposure leads to fear and through which fear extinction resolves these fear states. Extinction is generally regarded as new inhibitory learning, but where the inhibition originates from remains to be determined. Gamma-aminobutyric acid (GABA), the primary inhibitory chemical messenger in the brain, seems to be very important to these processes.
A new article in Biological Psychiatry examined whether during the extinction of fear learning, GABA receptors may be inserted into the cell surface to reduce the excitability of the amygdala. Researchers inactivated a protein that links GABAA receptors to the cell surface. They found that this protein prevented fear extinction training and the local application of NMDA from increasing the number of GABAA receptors on the cell surface and enhancing the inhibition of amygdala nerve cells.
Lin and colleagues show that during fear conditioning, the number of GABAA receptors on the surface of neurons in the amygdala decreases, reducing the extent of inhibition of the neurons in this brain "fear center." When fear is extinguished by dissociating fear cues from unpleasant stimuli, the number of GABAA receptors on the cell surface of the amygdala neurons increases.
How does this happen? The study provides evidence of molecular mechanisms that shuttle GABAA receptors to the cell surface during extinction. The researchers showed that by inactivating a protein involved in the localization of GABAA receptors in the amygdala, they prevented the recruitment of GABA-mediated inhibition and extinction of fear. Dr. John Krystal, Editor of Biological Psychiatry comments: "This research provides evidence that we are starting to untangle the molecular mechanisms through which our cognitive and behavioral therapies might alter brain function."
1.Hui-Ching Lin, Sheng-Chun Mao, and Po-Wu Gean.
Block of γ-Aminobutyric Acid-A Receptor Insertion in the Amygdala Impairs Extinction of Conditioned Fear.
Institute of Basic Medical Sciences and Department of Pharmacology, Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan.