(Great Neck, NY - February 1, 2010) — Researchers at Medical College of Georgia have created what appears to be a mouse with schizophrenia by reducing the inhibition of brain cells involved in complex reasoning and decisions about appropriate social behavior.
"We believe the mouse, which exhibits some of the same aberrant behavior as patients with this disorder, will help identify better therapies," said Dr. Lin Mei, a developmental neurobiologist who directs MCG's Institute of Molecular Medicine and Genetics. Dr. Mei received NARSAD's Distinguished Investigator Award in 2008 to fund this study. "We are doing testing to see if antipsychotic drugs already on the market are effective in treating the mouse," he added.
MCG scientists made the mouse by deleting a candidate gene for schizophrenia, ErbB4, from interneurons, which are brain cells that help shower larger decision-making neurons, called pyramidal cells, with inhibition.
In their earlier work, they identified how ErbB4 and another candidate gene, neuregulin-1, work together to balance the activity of these pyramidal cells. They reported in Neuron in May 2007 that the two help keep a healthy balance between excitation and inhibition by increasing release of GABA, a major inhibitory neurotransmitter in the inhibitory synapses of the brain's prefrontal cortex. Seven years earlier, they showed the two also put a damper on excitatory synapses, communication points between neurons where the neurotransmitter glutamate excites cells to action.
To further test these findings, this time they altered the natural check and balance in cells directly involved with supplying pyramidal neurons with the inhibitor GABA. They did this by knocking out the ErbB4 gene in nearby chandelier and basket interneurons that supply GABA to pyramidal cells. "If we take out ErbB4 in these two interneurons, the neuregulin should have no effect because it can't promote GABA," Dr. Mei, Georgia Research Alliance Eminent Scholar in Neuroscience, said.
His postulation played out in the behavior of the mouse, who exhibited schizophrenia-like behavior including increased movement and impaired short-term memory. The scientists are still gathering data on the manic aspect of schizophrenia in their mice.
Published in the Dec. 28 issue of the Proceedings of the National Academy of Sciences (PNAS), the findings reveal the critical balance between excitation and inhibition of these cells that appears to go awry in schizophrenia. They also provide the first animal model for studying the disabling psychiatric disorder that affects about 1 percent of the population.
Dr. Mei suspects that if he could look at the chandelier and basket interneurons in the prefrontal cortex of schizophrenics, he would also find something wrong with their usual role of sensing the need for the inhibitor GABA and supplying it to the pyramidal cells. "In schizophrenia, the baseline of the excitatory neurotransmitter is probably high," he said.
Co-authors include MCG scientists Drs. Wen-Cheng Xiong, Alvin Terry and Almira Vazdarjanova and postdoctoral fellows Drs. Lei Wen, Yi-Sheng Lu and Xin-Hong Zhu.
(This study was adapted from the Medical College of Georgia.)
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