Genetic trigger for schizophrenia affirmed

30 November 2018

A research team led by Dr Hannah Xue (Croucher Senior Research Fellowship 2005), of the Hong Kong University of Science and Technology, has solved an important genetic mystery related to the chronic mental disorder of schizophrenia. 

The team has completed studies that show the disease can be triggered by genetic factors alone. Until now, scientists had understood that both genetic and environmental factors could influence the disease development, but were uncertain whether a genetic mutation alone would initiate the symptoms.

Schizophrenia affects about one per cent of the general human population, translating into millions of sufferers, who may experience a combination of hallucinations, delusions, and extremely disordered thinking and behaviour that impairs daily functioning.

The researchers investigated the function of GABRB2, a gene already known to be associated with the disease, by inactivating one or both copies of the equivalent Gabrb2 gene in mice and examining the consequences. The findings have been published in Translational Psychiatry.

In a range of behavioural tests, both types of knockout mice were found to display schizophrenia-like symptoms. These included prepulse inhibition deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, and accelerated pentylenetetrazol (PTZ)-induced seizure.

The symptoms were most severe in the two-copy knockout mice, which were also highly susceptible to audiogenic epilepsy, a type of seizure induced by a loud sound and thought to be related to schizophrenia.

The researchers observed similar changes in the brains of the knockout mice to those found in human schizophrenia. These included a reduction of newborn neurons in the hippocampus, and extensive neuro-inflammation demonstrated, for example, by over-activation of microglia scavenger cells and enhanced oxidation stress. Moreover, the schizophrenia symptoms were ameliorated by the antipsychotic drug risperidone.

Since 2003, Xue and her research group have been at the forefront of research on the GABAa receptor and changes in the GABABR2 gene, which have been strongly associated with schizophrenia in multiple ethnic groups. “After 15 years’ extensive in vitro studies on this same gene, we have finally confirmed the importance of this discovery in a live animal model,” she said.

“The results suggested that the loss of the Gabrb2 gene alone was sufficient cause of the schizophrenia-like symptoms,” Xue explained. “This convergence of human and animal evidence pinpointing the involvement of GABRB2 in the development of schizophrenic symptoms establishes a GABRB2-origin of schizophrenia.”

It also opened the way to further research and understanding of the pathophysiological mechanisms that underlie schizophrenia, she said.

Professor CY Liu, of The State University of New York Upstate Medical University commented: “ This research has provided valuable insight into the role of GABA-A receptor beta-2 subunit in the origin of schizophrenia. Using a Gabrb2-knockout mouse model, they demonstrated that the dosage of this receptor can affect animal behaviour. The most intriguing part of their story is that schizophrenia-related behaviour, epilepsy, neuroinflammation, antipsychotic response all come together nicely in this model. Even though human schizophrenia patients may not have the exact dosage deficit of this GABA receptor subunit in the knockout mice, it is possible that at least some patients have risk genes that can be mapped on to this pathway. Therefore, this knockout mouse model will be useful for us to understand parts of the disease etiology and has a potential to be used for screening new drugs for treating schizophrenia and related disorders."

Dr Hannah Xue received her PhD in Biochemistry from the University of Toronto. She joined Hong Kong University of Science and Technology in 1994 and currently serves as professor in the Division of Life Science and director of the Applied Genomics Center. She was awarded a 2005-2006 Croucher Senior Research Fellowship and 2010 Higher Education Outstanding Scientific Research Output Award (Science and Technology) in Natural Sciences. Her current research includes deciphering the genetic causes of human complex diseases, including cancers and mental disorders, using cutting-edge genomic and bioinformatics technologies, as well as studying the active constituents of Chinese herbal medicine and their chemical derivatives through in vitro and in vivo molecular pharmacology approaches.

To view Dr Xue’s Croucher profile, please click here.