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Karoly Mirnics, M.D., left, Krassimira Garbett, Ph.D., and colleagues are developing new ways to generate animal models to study complex brain disorders. (photo by Susan Urmy)

New tool for modeling brain disorders created

BY: LEIGH MACMILLAN

3/05/2010 - It's hard to know if a mouse feels paranoid, hears voices or experiences the cognitive symptoms of schizophrenia. So developing a mouse model for this disorder is tricky.

But mouse models (or any animal models) of schizophrenia and other complex brain disorders are precisely what are needed to unravel the pathology of these disorders and find more effective treatments.

Now, Karoly Mirnics, M.D., professor of Psychiatry, and colleagues, have developed a novel strategy to generate mouse models for studying complex brain disorders.

They used the new tool, described in the journal Molecular Psychiatry, to reduce the expression of a gene in a select set of neurons, to mimic one of the brain deficits observed in schizophrenia.

“As a field, we came to the conclusion that we can't mimic schizophrenia in a mouse,” said Mirnics, who is also a Vanderbilt Kennedy Center investigator.

“What we can do is mimic certain pathophysiological processes that are related to schizophrenia in humans and then try to put together from many different mouse models what is really going on in the human brain.”

To choose which pathophysiological processes to mimic, the investigators examined gene expression patterns in postmortem brain tissue from patients with schizophrenia.

Mirnics explained that gene expression patterns reflect the “sum of lifetime events” that have occurred in the patient's brain.

“Gene expression is a convergence point between genetic and environmental insults,” he said.

“We don't exactly know what those insults were, but we can see their 'signature.' If this signature is what produces the symptoms of the disease, then that's what we want to mimic in an animal model.”

The most consistent findings in human postmortem brains have been deficits in “interneurons” that release the inhibitory neurotransmitter GABA, in particular a reduction in the levels of the GABA-producing enzyme GAD1.

Interneurons are an “integrative force in the brain's cortex — they likely define our working memory, which suffers devastating losses in schizophrenia,” Mirnics said.

He and his colleagues decided to systematically reduce GAD1 levels in different populations of mouse interneurons.

To do this, they created a new molecular strategy for making a transgenic mouse (a mouse with an introduced gene “construct”).

Their construct included: a bacterial artificial chromosome (BAC) to direct expression to various subsets of interneurons; a microRNA to block expression of GAD1; and a gene for the fluorescent protein GFP to allow visual identification of the targeted neurons by their fluorescent “glow.”

The researchers demonstrated that the new approach reduced the levels of GAD1 in interneurons that express a protein called neuropeptide Y. They also are targeting other groups of interneurons, and they are beginning to characterize the new mouse models and define “what these neurons do in the brain, and how the mouse behaves if we inactivate these neurons,” Mirnics said.

Using multiple types of animal models, Mirnics hopes the team will be able to “dissect the functions of these specific populations of interneurons and how they relate to behavioral deficits in schizophrenia, and ultimately find drugs that will counterbalance the deficits in these neuronal populations.”

The new technology “has enormous potential for making animal models because it allows the researcher to target any gene for silencing in a cell type specific way,” Mirnics said.

“It's not limited to psychiatry disorders, but can be used for virtually any type of disease model.”

He noted that the new approach is faster and less costly than mouse knockout technologies, and that it offers investigators the advantage of being able to see the cells that have been targeted (because of the fluorescent marker).

He also suggested that a single construct could include multiple microRNAs to block the expression of more than one gene in a targeted cell.

Krassimira Garbett, Ph.D., Szatmar Horvath, M.D., Ph.D., and Phil Ebert, Ph.D., were key to the success of the studies.

The research was supported by the National Institutes of Health, the Vanderbilt Kennedy Center, and NARSAD.

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