August 23, 2005

Success in Animal model of Schizophrenia

Read more... Schizophrenia Biology

Study Finds Neural Abnormalities are the Same in Animal Model and Postmortem Schizophrenia Brains - Findings pave the way for developing new treatment strategies for schizophrenia

In a press release from McLean Hospital, Researchers at the Harvard-affiliated hospital report being able to produce cellular changes in rats' brains similar to those seen in humans with schizophrenia by manipulating a precise area of the animals' amygdala, a region critical to emotional stress and learning.

In a paper published in the online early edition of the Proceedings of the National Academy of Sciences (PNAS), the researchers, headed by Francine M. Benes, MD, PhD, director of McLean's Program in Structural and Molecular Neuroscience, reported establishing for the first time a direct link between findings seen in the postmortem brains of individuals with schizophrenia and electrophysiological recordings in rats' brains after experimentally-induced simulations.

"This is a first for this field," said Benes, also a professor of psychiatry at Harvard Medical School. "The ability to predictably induce changes in the rat model makes it possible to develop new molecular strategies for the treatment of schizophrenia, ones that are based on specific changes in neural circuitry within the brain."

This work is based on 15 years of Benes' studies on the brains of deceased patients with schizophrenia. The studies had been able to identify discrete abnormalities in the circuitry of three brain regions in the limbic lobe, an area that is key to emotions and learning, functions that are abnormal in those with schizophrenia.

Based on those findings, the authors hypothesized that these changes or abnormalities may have been linked to excessive electrical input from the amygdala region of the brain to the hippocampus, which is part of the limbic lobe and plays an important role in emotional stress and learning.

To test the idea, the McLean Hospital researchers developed a rat model where they were able to stimulate increased electrical activity originating in the amygdala and found that this stimulation produced changes in a type of neuron called a GABA cell. These changes were similar to those that had been seen in humans with schizophrenia. Based on the new PNAS study, Benes speculates that these changes in the electrical properties of hippocampal GABA cells would probably interfere with emotional responses and learning, particularly under stressful conditions.

"This work points to a particular piece of circuitry as being important in neuronal malfunctions in schizophrenia," Benes said.

Postmortem studies of schizophrenia have been hampered by the lack of functional information regarding hippocampal GABA cells, she said. To fill in those gaps, co-authors Barbara Gisabella, PhD, and Vadim Bolshakov, PhD, researchers at McLean's Mailman Research Center, used sophisticated electrophysiological techniques to demonstrate deficiencies in GABA functioning in the new rat model of schizophrenia.

Benes said the work means that the animal model can be used to learn more about how limbic lobe circuitry functions under both normal and abnormal conditions. Additionally, new technologies, such as gene expression profiling, can be used to look at how thousands of genes inside specific neurons, such as GABA cells, are undergoing functional changes related to the altered circuitry. She noted that a 1998 study showed there was increased metabolic activity in the hippocampus of schizophrenic patients. The electrophysiological recordings reported in the PNAS paper can help to explain this observation in live subjects.

"These new findings in rats that we report on in the PNAS are consistent with the idea that the increased metabolism seen in individuals living with schizophrenia may be related to GABA dysfunction," she said.


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