Fear of GAD

This year, FEBS Open Bio has started publishing summaries to highlight the societal impact of some of the journal's research articles. Here, we share an abridged version of the first summary, discussing a paper on fear authored by Professor Yuchio Yanagawa and colleagues.
Fear of GAD

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Anxiety, a symptom of many psychiatric disorders, is not only detrimental to the individual’s quality of life, but also places a heavy burden on friends, relatives, mental health services and the economy. While both psychological and pharmacological therapies are available for anxiety, these have associated risks (such as side effects and dependence after long‐term use) and may not be effective in all cases. A greater understanding of how the brain normally regulates fear would help researchers develop more selective treatments with reduced adverse effects.

Our nerve cells, or neurons, communicate with each other using various small molecules, known as neurotransmitters. One of the main neurotransmitters in the brain and spinal cord is called γ‐aminobutyric acid, or GABA, and this molecule is known to be important for the control of fear in the amygdala. Our bodies produce GABA using an enzyme called glutamic acid decarboxylase, or GAD. Two different genes encode slightly different versions of GAD: a larger form, called GAD67, and a smaller form, called GAD65. 

One way to investigate the role of an enzyme is to generate mutant mice which lack it and then examine their behaviour. This strategy worked for the shorter GAD65 enzyme: mice without a functional copy of GAD65 exhibit increased anxiety‐like behaviour and an increase in generalised fear. Unfortunately, mice lacking GAD67 die soon after birth and so the role of this enzyme in fear and anxiety is less well understood than that of GAD65.

Previously, technical limitations largely restricted genetic engineering to certain well‐studied model organisms, such as mice. However, a recently developed technique, called CRISPR, has enabled researchers to easily (relatively speaking…) modify gene sequences in various organisms, including rats. A team of researchers led by Professor Yuchio Yanagawa at Gunma University, Japan, recently took advantage of this technique to see if the effect of GAD67 could be studied in rats instead of mice. To their surprise, about 33% of mutant rats lacking GAD67 survived to adulthood.

The researchers used their newly generated strains to determine whether the absence of GAD67 affected the ability of rats to learn to associate certain events (such as the test cage or a tone with a particular frequency) with a mild electric shock. The mutant rats exhibited increased and unusual patterns of freezing as compared to control rats, suggesting that the lack of GAD67 enhances fear responses.

The full summary can be read here:  https://doi.org/10.1002/2211-5463.13104

The research article can be read here: https://doi.org/10.1002/2211-5463.13065

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