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TheAb mice bear a lot for science, but there is often (temporary) compensation: an almost miraculous cure for diseases that kill people. Unfortunately, the experimental drugs that cured millions of mice with Alzheimer's disease, schizophrenia or glioblastoma healed zero – which is sad. For many brain disorders, mice are poor role models of how humans will react to a drug.
Scientists have now discovered a key reason for this mouse-human disconnect, they reported on Wednesday: fundamental differences in the types of cells of the cerebral cortex of each species and, in particular, in the activity of key genes in these cells.
To this day, in the most detailed taxonomy of the human brain, a team of researchers the size of a symphony orchestra was sorting brain cells not according to their shape and location, as scientists have been doing since decades, but depending on the genes used. Among the key findings: Mouse and human neurons considered to be the same on the basis of such standard classification schemes may exhibit significant differences (tenfold or more) in the expression of essential brain component genes such as receptors. neurotransmitters.
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This makes the neurons and circuits that connect brain regions, which have long been believed to be essentially identical in mice and humans, are fundamentally different. And that could explain the abysmal record of drug development for neuropsychiatric diseases such as schizophrenia, depression, bipolar disorder, and autism.
"All the drugs that people are trying to develop are acting on receptors or other molecules," said neurobiologist Ed Lein of the Allen Institute for Brain Science in Seattle, who led the study, published in the journal Nature . "If the neurotransmitter receptor you hope to target is not used in the same cells in humans as in mice, your medicine will be in the wrong circuit" and will not have the same effect in patients than in laboratory rodents.
Knowing the many similarities in the brains of mice and humans, and these differences, should help those who develop drugs for brain diseases "to better use mouse models," said neuroscientist Dr. Eric Nestler of Icahn Medical School, Mount Sinai. did not participate in the new study. "This type of highly detailed molecular biology is a useful roadmap and will shed much more light on the validity of animal models of brain disorders.
This validity leaves a lot to be desired. Last year, scientists described the development of neuropsychiatric drugs as "in the middle of a crisis" because of all the discoveries made on the mouse that fail to be passed on to people. Of 100 neuropsychiatric drugs tested during clinical trials – usually after they "function" in mice, only nine become approved drugs, one of the lowest rates of all categories of diseases.
Among the many reasons for this, there are basic principles such as "irritability", "compulsiveness" or even depression in something with mustaches and a tail, wrote Nestler and a colleague in 2010. They knew how brains of mice and genetically different are genetically gained. This problem could not be solved, but it could help scientists to unravel the fundamental differences between the neurobiology of the two species.
"If you want to cure diseases of the human brain, you must understand the uniqueness of this brain," said Christof Koch, co-author of the study, chief scientist and president of the Allen Institute.
For their study, Lein and colleagues isolated cells – 15,928 of them – from the brains of deceased persons 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 for thought, emotions, memory, and other higher functions. The cortex is also where, if things go wrong, the result is a neuropsychiatric disease.
The 75 distinct types all had a corresponding mouse version, measured by the genes they used. But in many of these "homologous" cells, there were considerable differences in the levels of gene expression. In some cases, 18% of the genes had a difference of at least 10 times the level of expression between the mouse and the man.
Differences in the list of genetic components of brain cells "are likely to be functionally relevant because divergent genes are associated with connectivity and signaling," scientists wrote in Nature.
Among the biggest differences: which neurons express genes for neurotransmitter receptors (the molecules that neurons use to communicate via these chemicals) and for the proteins that link neurons into functional circuits.
Serotonin receptors, for example, allow neurons to react to this neurotransmitter and play a role in appetite, mood, memory, sleep and other brain functions. Both species have serotonin receptors, but in different types of neurons. To a lesser extent, gene expression for glutamate receptors, a neurotransmitter, also differs significantly between neurons in the human brain and those in the homologous mouse.
"The hypothesis with model organisms is that neurotransmitters have receptors on the same neurons as humans," Lein said. As this is apparently not the case, this suggests that "serotonin or glutamate could have very different effects in humans and in mice". It also means that a drug acting on the circuits of serotonin or glutamate could affect the mouse very differently. Human.
"I think their findings are in line with what we said nine years ago," Nestler said. Mice and other laboratory animals "will be useful models for neuropsychiatric diseases, but you need to look at them soberly."
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