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Study can show why drugs cure brain disease in mice, but not in ours



L Ab mice suffer a lot from science, but there is often a (temporary) compensation: an almost miraculous cure for diseases that kill people. Unfortunately, experimental drugs that have cured millions of mice with Alzheimer's disease or schizophrenia or glioblastoma have not healed people – reflecting the sad fact that for many brain disorders, mice are pretty lousy models of how people respond to a drug.

Scientists have now discovered a major reason for this separation between mouse and human, as they reported on Wednesday: Fundamental differences in the types of cells in the cerebral cortex of each species, and in particular in the activity of the key genes of these cells.

The most detailed taxonomy of the human brain so far, a research team the size of a symphony orchestra has not sorted brain cells by their shape and location, as scientists have done for decades, but by the genes they use. Key findings include: Mouse and human neurons, considered to be the same by such standard classification schemes, may have large (ten-fold or greater) differences in the expression of key brain components such as neurotransmitter receptors.

This distinguishes neurons and circuits that connect brain regions that have long been thought to be essentially identical in mice and humans. And it could explain the abysmal course of drug development in neuropsychiatric conditions such as schizophrenia, depression, bipolar disorder and autism.

"All drugs people try to have an effect on receptors or other molecules," said neurobiologist Ed Lein of Seattle's Allen Institute for Brain Science, which published the study, published in the journal Nature. "If the neurotransmitter receptor you want to target is not used in the same cells in humans as it is in mice, your drug will hit the wrong circuit" and will not have the same effect on patients as on laboratory rodents. 1

9659003] The knowledge of the far-reaching similarities in the brain of mice and humans as well as the differences should help those who develop drugs for brain diseases, "to make better use of mouse models," said the neuroscientist. Eric Nestler from the Icahn School of Medicine at Mount Sinai, who was not involved in the new study. "This type of highly detailed molecular biology is a useful roadmap and will greatly enhance the validity of animal models of brain disorders."

This validity leaves something to be desired. Last year, scientists described the development of neuropsychiatric drugs as "in the midst of a crisis," as all mouse findings could not be transferred to humans. Of the 100 neuropsychiatric drugs tested in clinical trials, usually after they "work" in mice, only nine are approved, one of the lowest rates in all disease categories.

  Human Cell Micro
A human brain cell from the Middle Temporal Gyrus, involved in speech and other cognitive functions. Allen Institute

Among the many reasons for this are such basics as "irritability" or "obsession" or even depression in something with whiskers and Nestler and a colleague wrote a dick in 2010. Knowing how mouse brains and human brain are genetically different will not solve this problem, but it could help scientists unravel fundamental differences between the neurobiology of the two species.

"If you want to cure diseases of the human brain, you have to understand the uniqueness of the human brain," said study author Christof Koch, chief scientist and president of the Allen Institute.

In their study, Lein and his colleagues isolated 15,928 cells from the brain of deceased humans and from tissue removed during epilepsy surgery. All cells came from a region (called the middle temporal gyrus) of the human cerebral cortex, the brain's mission control of thoughts, emotions, memory, and other higher order functions. In the cortex, it also comes to neuropsychiatric diseases, if something goes wrong.

The 75 different types all had a suitable mouse version, measured by the genes used. In many of these "homologous" cells, however, there were dramatic differences in gene expression. In some cases, 18 percent of the genes showed at least a 10-fold difference in the level of expression between mice and humans.

The differences in the genetic parts list of brain cells are likely to be "functionally relevant because they are different genes linked to connectivity and signaling," the scientists wrote in Nature.

Among the biggest differences are the genes for neurotransmitter receptors (the molecules neurons communicate with via these chemicals) and proteins that bind neurons to functional circuits.

Serotonin receptors, for example, allow neurons to respond to this neurotransmitter and play a role in appetite, mood, memory, sleep and other central brain functions. Both types have serotonin receptors, but in different types of neurons. To a lesser extent, the expression of genes for receptors for the neurotransmitter glutamate differed significantly between homologous neurons of the mouse and the human brain.

said. Since this does not appear to be the case, it suggests that "serotonin or glutamate can have a very different effect in humans than in mice." This, in turn, means that a drug that works on serotonin or glutamate circuits has a Mouse can affect completely differently than a human.

"I think their results support what we said nine years ago," Nestler said. Mice and other laboratory animals will be "useful models for neuropsychiatric disorders, but you must consider them sober."


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