A mouse model for mental health

The Medical Science Building at the University of Toronto has a basement full of mice –with good reason.

Mice are one of the best-understood animals in science. They were among the first  to have their genome mapped. Since the 1980s, scientists have genetically engineered mice for research.

Even with all we know about mice, the idea of using the little critters to study schizophrenia, a complicated mental disorder, is hard to understand.

One per cent of Canadians are affected by schizophrenia, according to the Centre for Addiction and Mental Health. The illness disrupts the connection between brain cells, causing symptoms including social withdrawal, impaired memory and hallucinations – many of which cannot be treated by current medications.

“We can study some aspects of mental illness in mice, even though we can’t study hallucinations or hearing voices that aren’t there. Those of course are impossible to study in a mouse,” said Dr. Amy Ramsey, an assistant professor at U of T’s Department of Pharmacology and Toxicology. “We have been able to use tests to study different aspects of cognition.”

Ramsey was part of the team that genetically engineered NR1-KD, a mouse model for schizophrenia at Duke University in 1999. She brought the mouse model with her when she moved to Toronto.

Over the last decade, her study of NR1-KD provided a window into how schizophrenia distorts the wiring of the brain. Most recently, she’s looking into whether the brain can rewire after the damage is done.

Even though schizophrenia affects brain development from conception, the symptoms are usually only detected in late adolescence. Most  brain wiring happens in the first few days of the mouse’s life.

“By giving some drug or treatment in adulthood, have we missed this window of opportunity where the brain is more flexible?

” Ramsey said.

While a treatment that could stop the progression of schizophrenia doesn’t exist yet, Ramsey can still study  the question using NR1-KD.

The NR1-KD model has suppressed levels of N-methyl D-aspartate (NMDA) receptor 1, a protein that helps strengthen connections between neurons in the brain. Ramsey and her team focused on NMDA because people with schizophrenia have reduced NMDA levels.

To suppress NMDA, the researchers added a sequence of “junk DNA” to the genome to interrupt the copying process.

The lower NMDA levels have been linked to brain chemistry and behaviours that resemble symptoms of human schizophrenia, including mis-wiring of the brain, decreased working memory and social withdrawal.

However, some argue that since NR1-KD’s symptoms aren’t triggered by one of he genes suspected of making humans susceptible to schizophrenia it isn’t a true model of schizophrenia.

That’s beside the point, according to Lalit Srivastava, a professor at McGill’s Douglas Mental Health University Institute. He researches schizophrenia’s effects on brain development and has written about the use of various animal models in the field.

“We’re not just miniaturizing schizophrenia in a small mouse, we’re using it as a tool to ask certain questions we could not otherwise ask.”

This is where knowing the gene that suppresses NMDA levels in NR1-KD helps.

Kasia Mielnik, a graduate student who works under Ramsey, is making a new version of the mouse. She’s adding bookmarks to the chapter of junk DNA, so it can be removed later in the mouse’s development. This should stop the suppression of NMDA.

They will test removing the junk DNA at various ages. This will allow Ramsey and Mielnik to look at whether a mouse brain that never had normal NMDA levels will rewire itself or compensate for previous mis-wiring, using the same chemical and behavioural tests they used on NR1-KD.

While it’s a long way from a clinical application, it’s a tiny but important step in basic research.

Story produced by Adrianna Banaszek





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