Such behaviors are called endophenotypes. Now, researchers at the California Institute of Technology (Caltech) have found that mice lacking a gene that encodes a particular protein found in the synapses of the brain display a number of endophenotypes associated with schizophrenia and autism spectrum disorders.
The new findings appear in a recent issue of the Journal of Neuroscience, with Mary Kennedy, the Allen and Lenabelle Davis Professor of Biology at Caltech, as the senior author.
The team created mutations in mice so that they were missing the gene for a protein called densin-180, which is abundant in the synapses of the brain, those electro-chemical connections between one neuron and another that enable the formation of networks between the brain's neurons. This protein sticks to and binds together several other proteins in a part of the neuron that's at the receiving end of a synapse and is called the postsynapse. "Our work indicates that densin-180 helps to hold together a key piece of regulatory machinery in the postsynaptic part of excitatory brain synapses," says Kennedy.
In mice lacking densin-180, the researchers found decreased amounts of some of the other regulatory proteins normally located in the postsynapse. Kennedy and her colleagues were especially intrigued by a marked decrease in the amount of a protein called DISC1. "A mutation that leads to loss of DISC1 function has been shown to predispose humans to development of schizophrenia and bipolar disorder," Kennedy says.
In the study, the researchers compared the behavior of typical mice with that of mice lacking densin. Those without densin displayed impaired short-term memory, hyperactivity in response to novel or stressful situations, a deficit of normal nest-building activity, and higher levels of anxiety. "Studies of mice with schizophrenia and autism-like features have reported similar behaviors," Kennedy notes.
"We do not know precisely how the molecular defect leads to the behavioral endophenotypes. That will be our work going forward," Kennedy says. "The molecular mechanistic links between a gene defect and defective behavior are complicated and, as yet, mostly unknown. Understanding them goes to the very heart of understanding brain function."
Indeed, she adds, the findings point to the need for a better understanding of the interactions that occur between proteins at synapses. Studies of these interactions could provide information needed to screen for new and better pharmaceuticals for the treatment of mental illnesses. "This study really reinforces the idea that small changes in the molecular structures at synapses are linked to major problems with behavior," Kennedy says.
Caltech coauthors of the paper, "Deletion of Densin-180 Results in Abnormal Behaviors Associated with Mental Illness and Reduces mGluR5 and DISC1 in the Postsynaptic Density Fraction," include Paul Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences; Holly Carlisle; Tinh Luong; Andrew Medina-Marino; Leslie Schenker; Eugenia Khorosheva; Keith Gunapala; and Andrew Steele. The paper's other authors are Tim Indersmitten and Thomas O'Dell of the David Geffen School of Medicine at the University of California, Los Angeles. The work was supported by the National Institutes of Health, the Gordon and Betty Moore Foundation Center for Integrative Study of Cell Biology, the Howard Hughes Medical Institute, the National Science Foundation, the McGrath Foundation, and the Broad Fellows in Brain Circuitry program.
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