Science Update June 26, 2008
Mice Expressing Human Genes Bred to Help Unravel Mental Disorders
New mouse strains engineered to express human genes related to mental disorders are being developed under a recently-launched grant program from NIMH’s Division of Neuroscience and Basic Behavioral Science. The new models are designed to help scientists understand the molecular workings of variations in genes that may predispose for – or even help protect against – illnesses like depression, bipolar disorder and schizophrenia. They will also explore how duplications or the differences in the amount of genetic material affect brain function, and how genes influence response to treatments.
The new studies follow a spate of recent discoveries using such mouse models to replicate features of mental and developmental disorders. So far, eight new grants have been awarded in response to an NIMH program announcement issued last year.
“Knock-In” to Model Bipolar Features
In one of the newly launched studies, Elizabeth Simpson, Ph.D., of the University of British Columbia, is following-up her recent discovery* of eight variants of a suspect gene in people with bipolar disorder, schizophrenia and aggressive disorders that were not found in healthy controls. Conserved through evolution, this gene is important for brain development and birth of new neurons in both the mouse and human forebrain. Simpson initiated her search for variants in humans after finding that mice lacking the gene are hyperactive, aggressive and otherwise behaviorally impaired.
Instead of such a “knock-out,” her new study will “knock-in” combinations of the suspect human gene variants in an effort to create mouse strains that mimic features of the mental illnesses, particularly bipolar disorder. The researchers will generate five different mouse strains and test them for differences in brain systems, behavior, and any effects of the gene variants on response to lithium, the medication commonly used to prevent episodes of mania and depression. They hope their findings will ultimately contribute to better diagnosis and treatment of the disorder.
Depression Gene Riddle Examined in Mouse Embryonic Stem Cells
In another of the newly-funded studies, Beverly Koller, Ph.D., of the University of North Carolina, will genetically engineer mice to express human gene variants at the center of a controversy in psychiatric genetics.
A series of studies has implicated in depression one of two common versions, called the short variant, of a gene that produces a protein that recycles the chemical messenger serotonin. The most widely prescribed class of antidepressants act by blocking this serotonin transporter protein, suggesting a pivotal role for the protein in the disorder. However, the short variant’s statistical association with depression remains in dispute. Also, determining how it might work differently than the long variant to affect serotonin function and behavior has proven difficult in living organisms – especially if the difference stems from how the gene is expressed rather than the structure of the encoded protein.
To address this issue, Koller has devised a unique method for replacing the mouse serotonin transporter gene with either the short or long version of the human gene in mouse embryonic stem cells. This will yield mouse strains that differ only in the precise variation associated with risk for depression in humans, permitting any effects on protein function, development and behavior to be detected.
Schizophrenia Features Produced in Mice by Candidate Gene
Among recent discoveries made possible by animal models similar to those discussed above, versions of a gene implicated in schizophrenia were found to trigger behaviors and neurological features characteristic of the human illness in mice. Two separate teams of NIMH-supported researchers at Johns Hopkins University produced somewhat different components of the human illness in genetically-engineered mouse strains with the gene, called DISC1 (for Discovered In Schizophrenia).
The DISC1 gene codes for an enzyme in the brain’s cortex and hippocampus important for mood and memory, as well as for brain development. Different variants of the gene have been linked to schizophrenia and mood disorders in different samples.
Mikhail Pletnikov Ph.D., and colleagues, inserted altered forms of the human DISC1 gene into the forebrain of mice – areas comparable to the human circuits implicated in schizophrenia, creating strains with both strong and weak expression of the gene’s protein. Also, the timing of the expression was selectable, so it could be used to study the function of the DISC1 protein at various stages of prenatal development, when schizophrenia is thought to originate. Expression of the human mutant form triggered a significant decrease in expression of the mouse’s natural protein and other key proteins critical for normal brain development. As in human schizophrenia, there were sex differences in symptoms; male mice moved around more and socialized less, while female mice showed memory problems. Like humans with schizophrenia, the affected mice had enlarged ventricles and stunted neuron growth.**
In the other Hopkins study, Akira Sawa, M.D., Ph.D., and colleagues, showed both behavioral and anatomical features of schizophrenia, including enlarged ventricles (cavities filled with spinal fluid) and hyperactivity in genetically engineered mice with altered DISC1 genes. The animals also displayed anxiety and depression-like behaviors. The researchers point out that the differences seen are subtle, in keeping with the idea that additional genetic and/or environmental insults would be required for the full-blown syndrome. ***
*Kumar RA, McGhee KA, Leach S, Bonaguro R, Maclean A, Aguirre-Hernandez R, Abrahams BS, Coccaro EF, Hodgins S, Turecki G, Condon A, Muir WJ, Brooks-Wilson AR, Blackwood DH, Simpson EM. Initial association of NR2E1 with bipolar disorder and identification of candidate mutations in bipolar disorder, schizophrenia, and aggression through resequencing. Am J Med Genet B Neuropsychiatr Genet. 2008 Jan 18. [Epub ahead of print] PMID: 18205168
**Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2008 Feb;13(2):173-86, 115. Epub 2007 Sep 11. PMID: 17848917
***Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Epub 2007 Aug 3. PMID: 17675407
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