Washington: Researchers have discovered a new type of gene mutation that reduces fear and anxiety and also adds to social interaction in a development that could possibly help alleviate depression and social anxiety, conditions that affect over 300 million people globally.
The research published in the journal Neuropharmacology employed gene manipulation technology to remove the ‘P4h-tm’ gene from the mouse genome and found an unexpected change in mouse behaviour.
‘P4h-tm’ knockout mice showed striking courage and a lack of learned helplessness compared to congenic wild-type mice with a functional ‘P4h-tm’ gene.
The researchers assessed the mice with a large behavioural test battery that included a novel type of test for the panic reaction. The mice were placed in an air-tight box that was first filled up with regular room air and with 10 per cent carbon dioxide.
An elevated concentration of carbon dioxide induces an innate freezing reaction that is thought to resemble the feeling of suffocation in patients suffering from panic attacks.
‘P4h-tm’ knockout mice displayed substantially less freezing than control mice in response to carbon dioxide exposure. In tests for social interaction, ‘P4h-tm’ knockout mice made clearly more contact with another mouse than the controls.
In addition, behavioural tests routinely used for screening anti-anxiety and anti-depressant drugs revealed reduced fear, anxiety and learned helplessness in ‘P4h-tm’ knockout mice.
Further, the study found a connection between brain anatomy and the behavioural phenotype: the expression of the ‘P4h-tm’ gene was especially high in the amygdala that plays a key role in controlling emotional reactions, including fear and anxiety.
The ‘P4h-tm’ gene accounts for the transcription of the ‘P4H-TM’ protein. This protein belongs to the family of prolyl-4-hydroxylases that play a pivotal role in the cellular adaptation to a sudden lack of oxygen.
However, the ‘P4H-TM’ protein differs from other prolyl-4-hydroxylases in both its structure and unusual location (endoplasmic reticulum). The physiological role of the P4H-TM protein remains elusive despite years of intensive research, but it is assumed to have other effects on cellular biology besides adaptation to varying oxygen levels.
The researchers also tested the inactivation of three other known prolyl-4-hydroxylases in separate mouse lines. These mice did not show abnormal behaviour in the above-mentioned tests.
“Our findings are really interesting; we know that the deficiency of the ‘P4H-TM’ gene results in severe developmental defects in humans. However, in light of present knowledge, we cannot tell whether these harmful effects arise from embryonic development or whether they would also appear if the function of the ‘P4H-TM’ protein was inhibited in the adult age,” said Heikki Tanila, one of the researchers.
“We could best find an answer to this question by using conditional gene inactivation in which the gene could be turned off at any desired age,” Dr Henri Leinonen, the first author of the article, concluded.
“In an ideal experiment, ‘P4h-tm’ would be turned off only in the amygdala of an adult mouse,” Dr Leinonen added.
Anxiety disorders and depression are a huge global problem. According to the World Health Organization (WHO), almost 300 million individuals worldwide suffer from anxiety disorders, and over 300 million suffer from depression.