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Subtle Differences In Brain Cells Indicate Why Many Drugs Help Mice But Not People

Scientists have used mice to test a variety of drugs that treat brain disorders like depression,  schizophrenia and murine versions of Alzheimer’s disease. But these same treatments usually fail in people.

With new brain maps, researchers are now beginning to understand why.

A team reported last Wednesday in the journal Nature that their comprehensive comparison of the cell types in mouse and human brain tissue brought out subtle but important differences that possibly affect the response to many drugs,

Christof Koch, Chief scientist and President of the Allen Institute for Brain Science in Seattle and one of the authors of the study said, “If you want to develop a drug that targets a specific receptor in a specific disease, then these differences really matter”.

Ed Lein, a study author  and investigator at the institute explained that one significant difference involved genes that cause a cell to respond to the chemical messenger serotonin.

 

He elaborated, “They’re expressed in both mouse and human, but they’re not in the same types of cells.  As a result, serotonin would have a very different function when released into the cortex of the two species. That’s potentially a big deal because antidepressants like Prozac act on the brain’s serotonin system. So testing these drugs on mice could be misleading”.

Such a detailed comparison was possible because of new technology that enables scientists to quickly identify which of the hundreds of types of brain cells are present in a particular section of brain tissue.

The technology achieves this by detecting which genes are switched on in each cell indicating a typical genetic signature corresponding to the type of cell.

Lein says, “In one fell swoop you can get a more or less comprehensive understanding of all of the different types of cells that make up a brain region. This also makes it much easier to compare brain tissue from different species. We now have access to this fine level of resolution in the human brain and the ability to compare across and see how good a model a mouse or a monkey actually is”.

 

The list of cell types also should help researchers see what goes wrong in human brain disorders, Koch adds by saying, “A lot of neurological diseases, a lot of psychiatric diseases that we’re suffering from are due to specific defects in particular types of cells”.

For instance, Parkinson’s disease affects brain cells that produce a substance called dopamine while epilepsy encompasses special cells that tamp down brain activity.

Koch acknowledges that researchers now have a way to make sure whether the types of cells involved in a particular disease work the same way in people as in an animal trial or not.

Tomasz Nowakowski, an assistant professor of anatomy at the University of California, San Francisco who co-wrote an editorial that accompanied this study, said, “The technology finally caught up with what we’ve been needing to do for probably over 40 years “.

To compare human and mouse brain cells, researchers first investigated sixteen thousand human brain cells extracted from the middle temporal gyrus of the cortex i.e. the brain’s outermost layer. Then they examined cells taken from the same area of a mouse brain.

Noting that both mice and people had about 100 different types of cells in this region of the brain, Koch says, “In one sense, they are remarkably similar “.

But then a closer comparison of 75 of these brain cell types exposed small differences. The finding that cells named microglia have a slightly different genetic signature in mice and people has especially intrigued Nowakowsky.

He explained, “Those cells are the immune cells of the brain. And you might imagine that studies or insights into neuroimmune disorders, for example, might be vastly affected by this difference.”

Multiple sclerosis, amyotrophic lateral sclerosis, and systemic lupus are all neuroimmune disorders but there’s rising evidence that microglia also play an important role in Alzheimer’s disease.

This could be one reason why experimental Alzheimer’s drugs have not worked on people but helped mice.

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