News Release: Research

Nov. 5,  2010

Function Revealed for Gene with Many Links to Psychiatric Diseases

News Article ImageXiao-Jiang Li, MD, PhD

In the last few years, the gene Ahi1 has been linked to several disease conditions. Mutations in the gene cause Joubert syndrome, a developmental disorder that affects a child’s breathing and muscle control. In addition, subtle changes in the Ahi1 gene have been connected with schizophrenia and autism.

By studying mice with Ahi1 disabled in the brain, scientists at Emory University School of Medicine have revealed a critical function for the gene. The protein encoded by Ahi1 appears to recycle receptors or “receiver dishes” that allow brain cells to respond to growth signals. When Ahi1 is disabled in mice, the receptors are stuck inside brain cells, where they are digested. The altered mice display signs of depression in behavioral tests.

The results were published this week in the Proceedings of the National Academy of Sciences.

“While we had some idea of what Ahi1 does in the cell, we didn’t know how it functions in the brain or in the context of the whole animal,” says senior author Xiao-Jiang Li, PhD, professor of human genetics at Emory University School of Medicine. “Because the development of mouse models for depression that are responsive to treatment is still in its infancy, these mice could facilitate studies into the origins of depression and drug discovery efforts.”

The first author of the paper is Xingshun Xu, now a faculty member at the Institute of Neuroscience at Soochow University in China.

To focus on Ahi1’s function in the brain, the Emory team created a mouse where the Ahi1 gene is disabled in the brain only. In laboratory tests used to study depression in mice – the “forced swim” and “tail suspension” tests – Ahi1-disabled mice are more immobile than normal mice. These tests are thought to simulate “learned helplessness,” an aspect of depression. The altered mice do respond to the antidepressants imipramine and fluoxetine, becoming more mobile in the tests.

Scientists believe that a lack of the growth factor BDNF (brain derived neurotrophic factor) can lead to depression. Previous research by Li and colleagues suggested that Ahi1 was important for transporting BDNF receptors to the surfaces of neurons. The researchers found that the level of BDNF receptors is reduced in the brain, which may explain the signs of depression.

Li’s laboratory focuses on mechanisms of Huntington’s disease. He and his colleagues originally began investigating Ahi1 because it appears to work together with another protein, Hap1, whose function is disrupted in Huntington’s.

The results also suggest an explanation for why depression can be an early sign of Huntington’s disease. For schizophrenia and autism, the connection with Ahi1’s function is likely to be more complex, since both conditions are not caused by problems with a single gene, Li says. Hap1 and Ahi1 have also been shown to regulate other molecules such as neurotransmitter receptors, he says.

In people with Huntington's disease, the gene for the protein huntingtin carries a mutation that lengthens one section of the genetic code, so that three letters (CAG) are repeated dozens of times. This mutant huntingtin is “stickier” and clumps together inside brain cells and also interacts more tightly with Hap1, interfering with both it and Ahi1.

Hap1 and Ahi1 stabilize each other and work together; mutations in one cause reduction in the protein level of the other. Hap1 and Ahi1 appear in the same parts of the brain, but they don’t overlap completely. For example, mice with mutations in Hap1 die days after birth because of feeding problems, apparently because of degeneration of the hypothalamus, a part of the brain that regulates appetite. However, Ahi1-altered mice don’t have the same problems.

Previous research has shown that completely deleting the Ahi1 gene in mice results in blindness and cystic kidney disease. However, the mice do not display problems with movement that would resemble Joubert syndrome. This may be because the mouse brain develops differently from the human brain, Li says.

The research was supported by the National Institutes of Health.

X. Xu, H. Yang, Y.F. Lin, X. Li, A. Cape, K.J. Ressler, S. Li and X.J. Li. Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype. PNAS Early Edition (2010).

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The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service.

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