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Mental health means new neurons?

A gene strongly associated with schizophrenia and other neuropsychiatric disorders regulates the birth of new neurons in the adult brain, according to new research. linkurl:The study,;http://www.cell.com/fulltext/S0092-8674(09)00021-X published in Cell this week, supports a controversial theory linking diseases such as schizophrenia and depression to neurogenesis and provides new targets for the treatment of psychiatric conditions. Image: flicker/linkurl:Staurland;http://www.flickr.com/photos/

By | March 19, 2009

A gene strongly associated with schizophrenia and other neuropsychiatric disorders regulates the birth of new neurons in the adult brain, according to new research. linkurl:The study,;http://www.cell.com/fulltext/S0092-8674(09)00021-X published in Cell this week, supports a controversial theory linking diseases such as schizophrenia and depression to neurogenesis and provides new targets for the treatment of psychiatric conditions.
Image: flicker/linkurl:Staurland;http://www.flickr.com/photos/staurland3
"This is the first time anybody has ever shown that this protein [coded by the gene] directly regulates the number of neural progenitors," said linkurl:Li-Huei Tsai,;http://web.mit.edu/picower/faculty/tsai.html main author and neuroscientist at the Picower Institute of Learning and Memory at the Massachusetts Institute of Technology. Previous studies have linked schizophrenia to disturbances in neurogenesis in a brain region called the hippocampus and suggested that anti-depressant medications such as Prozac work by stimulating hippocampal neurogenesis. The new findings link the gene, DISC1, to a well-studied signaling pathway that controls neurogenesis and the development of the nervous system. "It really fits in with a lot of background information to suggest that hippocampal neurogenesis in particular is potentially a process which is going wrong in psychiatric illness," said linkurl:Ben Pickard,;http://www.schizophreniaforum.org/com/res/detail.asp?id={98699AC1-C5A8-4B00-B834-CE4937812B40} a medical geneticist at the University of Edinburgh who was not involved in the study. Researchers first made the link between DISC1 and psychiatric disorders linkurl:in 2001;http://www.ncbi.nlm.nih.gov/pubmed/11443544 -- a large Scottish family with a high incidence of schizophrenia and bipolar disorder displayed a specific translocation in the gene's sequence. Since then, Tsai and others have linked other mutations in the gene to psychiatric disorders. There have been suggestions that DISC1 is involved in linkurl:early cortical development;http://www.ncbi.nlm.nih.gov/pubmed/16299498 and linkurl:integrating;http://www.ncbi.nlm.nih.gov/pubmed/17825401 newly produced neurons in the adult brain, but "because there were no sequence matches in the database," explained Pickard, "it was very hard to figure out what it does." Tsai, who is a Howard Hughes Medical Institute investigator, and her colleagues showed that the DISC1 protein interacts with a protein called GSK3-beta, muffling its effect. The role of GSK3-beta is to inhibit the function of the protein beta-catenin, which promotes stem cell proliferation. In essence, the job of DISC1 is to inhibit the inhibition of neurogenesis. If a mutation in the gene is blocking the protein from doing its job, GSK3-beta is left exerting its inhibitory effect on neuronal growth, potentially causing different psychiatric illnesses. When the researchers silenced DISC1 in the hippocampus of adult mice using RNA interference, the mice showed symptoms associated with schizophrenia and depression. Interestingly, Pickard and Tsai noted that GSK3-beta is the molecular target of lithium, the most effective treatment available for bipolar disorder. Although the compound has been used for decades, how it works is largely unknown. Tsai's findings suggest that lithium's mechanism may involve stimulating neurogenesis. "One of the most exciting aspects of the study is the parallel between this one function and lithium," said Tsai. That knowledge may also provide a genetic means of predicting which patients will respond to lithium. Indeed, the clear link the study makes between the genetics and the pathophysiology is "giving us clues as to why the medications might work in some people and not in others," said linkurl:David Porteous,;http://www.cip.ed.ac.uk/members/not_HRB/porteous/index.htm a molecular geneticist also at the University of Edinburgh who was not involved in the present work, and who coauthored the original DISC1 family study. "In that regard, it's not just a very good piece of science; it's also giving us a roadmap to what we should be doing next." That will involve working out the fine details of how DISC1 and GSK3-beta work together, and how other molecules are involved, Porteous said -- a project which Tsai's lab is now working on. Three years ago, Porteous, Pickard and others implicated DISC1 in linkurl:another pathway;http://www.ncbi.nlm.nih.gov/pubmed/16293762 central to brain development. How the two interact may yield further clues to the molecular underpinnings of psychiatric illnesses. "We're starting to develop a kind of genetic network around the DISC1 pathway," he said, which points to "targets for intervention in a much more rational fashion than what's been possible."
**__Related stories:__***linkurl:Schizophrenia (special supplement);http://www.the-scientist.com/supplement/2007-12-1/
[December 2007]*linkurl:Growing a new antidepressant;http://www.the-scientist.com/2007/4/1/40/1/
[April 2007]
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Comments

Avatar of: Claire Seymour

Claire Seymour

Posts: 2

March 20, 2009

This is a very interesting story but it gives the impression that the role of GSK-3beta is regulation of beta-catenin and neurogenesis. This is too simplistic. GSK-3beta has many substrates including glycogen synthase (from which GSK-3beta gets its name), the micro-tubule associated protein tau and CREB. Hyperphosphorylated tau is the main component of paired-helical filaments which make up the tangles observed in Alzheimer's disease brains. CREB is a transcripition facter shown to be very important for memory processes. Indeed there is a great deal of research examining the role of GSK-3beta in Alzheimer's disease pathology.
Avatar of: Martin Walker

Martin Walker

Posts: 2

March 20, 2009

It seems to me that we're seeing an increasing body of work that is making excellent inroads into understanding the mechanisms around mental disorders. Great to see. Thanks for reporting.\n\nMartin Walker\nwww.mindsparke.com
Avatar of: Dr Cheng

Dr Cheng

Posts: 11

March 21, 2009

If you got strong computer science operating system background, you may find this analog very interesting, and maybe you shall have break through on the relation between schinophrensia and forking a subprocess.
Avatar of: Petra Moessner

Petra Moessner

Posts: 10

March 21, 2009

The last lab I worked in was a neuroscience lab and now I am retraining in computer science. I am currently taking an operating systems class and we are covering fork() in the Linux kernel. Fork() does create create new processes. Is that what you mean?
Avatar of: anonymous poster

anonymous poster

Posts: 4

March 23, 2009

To the best of my knowledge, this is not sorted out as of yet. I do believe some Morris water maze work indicates a role during specific points of learning, not sure which off the top of my head. But it seems like quite a jump to claim a role in psychiatric disorders. Would anyone fill me in on any evidence out there I don't know about?
Avatar of: Michael Corbin

Michael Corbin

Posts: 1

March 24, 2009

Have you thought about the stats showing a correlation of mental illness with early onset Alzheimers? Seems as if we might want to look into that relationship a little deeper.
Avatar of: anonymous poster

anonymous poster

Posts: 10

March 24, 2009

The difference between mental illness and early onset Alzheimer's is mental illness is treatable while Alzheimers isn't really. I am 48 and have bipolar and have experienced no cognitive decline because I am on medication.
Avatar of: anonymous poster

anonymous poster

Posts: 1

April 12, 2009

There is also an emerging body of research that shows that the auditory hallucinations experienced by some people with 'schizophrenia' are due to altered memory processing during trauma whereby the memory is re-called or experienced as an external voice rather than the usual internal thought processes. Would be interesting to look at this in relation to the biochemical processes involved in the conversion of short to long-term memory.

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