New mouse model shows that APC regulates proteins critical for normal learning, memory, and behavior
Autistic-like behaviors and decreased cognitive ability may be associated with disruption of the function of the Adenomatous Polyposis Coli (APC) gene. When Tufts researchers deleted the gene from select neurons in the developing mouse brain, the mice showed reduced social behavior, increased repetitive behavior, and impaired learning and memory formation, similar to behaviors seen in individuals with autism and intellectual disabilities.
This study is the first to evaluate how the loss of APC from nerve cells in the forebrain affects brain development, learning, and behavior. The research team, led by Michele Jacob, Ph.D., engineered a new mouse model for studying cognitive and autistic-like disabilities. The study was published online today in Molecular Psychiatry.
In addition to observing autistic-like behaviors and cognitive impairments in the mice, researchers found significant molecular changes in the brain. Eliminating APC chiefly from the excitatory neurons in the forebrain led to altered levels of specific proteins that regulate gene expression and influenced the structure, number, and function of synapses.
Some of these molecular changes have not been seen in other genetic mouse models of cognitive and autistic-like disabilities, but are likely relevant to the human disorders based on recently identified risk genes. The researchers propose that APC tightly regulates particular protein levels, maintaining them within a range that is critical to normal learning and memory consolidation.
"What makes this study interesting is that although there are hundreds of risk genes implicated in autism, the removal of this single gene produced a multi-syndromic disorder similar to that seen in individuals with both cognitive deficits and autism. The APC-deficient mice are noticeably different from normal mice in their impaired learning, poor memory consolidation, repetitive behaviors, and reduced social interest," said co-first author Jonathan Alexander, a Ph.D. candidate in neuroscience at the Sackler School of Graduate Biomedical Sciences at Tufts and a member of the Michele Jacob lab at Tufts University School of Medicine.
"This APC knock-out mouse is different because APC is eliminated from a specific type of cell in the brain during a critical period of development. This leads to deregulation of key signaling pathways and produces the cognitive and behavioral changes that we observed," explained co-first author Jesse Mohn, Ph.D., a graduate of the Sackler School and now a scientist at Galenea Corp.
"APC loss leads to molecular changes predicted to resemble, at least in part, those caused by spontaneous mutations in another gene, CHD8, recently identified as a high confidence risk factor for sporadic autism, that is, autism that arises spontaneously rather than inherited genetic mutations from parents. Thus, our findings are relevant to autism and intellectual disabilities caused by other human gene mutations, not only APC," said senior author Michele Jacob, Ph.D., professor of neuroscience at Tufts University School of Medicine, and member of the Cell, Molecular and Developmental Biology; Cellular and Molecular Physiology; and Neuroscience program faculties at the Sackler School.
"This study demonstrates the vital role that APC plays as a central hub that links to and regulates multiple signaling pathways within nerve cells that are essential for normal cognition and social behavior," added Antonella Pirone, Ph.D., a co-author and postdoctoral scholar in the Jacob lab. "We hope that identifying these novel molecular and functional changes caused by APC loss will contribute to the development of effective treatments for autism and cognitive impairments in patients."
Tufts University has filed patent applications claiming the use of the new mouse model for the screening of improved therapeutics.
Additional authors on the study are Christina D. Palka, B.S., a summer undergraduate research assistant; So-Young Lee, Ph.D., formerly a member of the Phillip Haydon lab at Tufts University School of Medicine; Leslie Mebane, Ph.D., former member of the Jacob lab; and Phillip G. Haydon, Ph.D., the Annetta and Gustav Grisard professor and chair of neuroscience at Tufts University School of Medicine, and member of the neuroscience faculty at the Sackler School.
This research was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under award numbers R01NS021725 and T32NS061764; and the National Institute of Deafness and other Communication Disorders (NIDCD) also of the NIH under award number R01DC008802. The Tufts Center for Neuroscience Research also supported this research through award number P30NS047243 from NINDS.
Mohn, JL, Alexander J, Pirone A, Palka CD, Lee S-Y, Mebane L, Haydon PG, Jacob MH, "Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities." Molecular Psychiatry, advance online publication, June 17, 2014, doi:10.1038/mp.2014.61
About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences
Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical and population health education and advanced research. Tufts University School of Medicine emphasizes rigorous fundamentals in a dynamic learning environment to educate physicians, scientists, and public health professionals to become leaders in their fields. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, the biomedical sciences, and public health, as well as for innovative research at the cellular, molecular, and population health level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical and prevention science.
Siobhan E. Gallagher | Eurek Alert!
Do microplastics harbour additional risks by colonization with harmful bacteria?
05.04.2018 | Leibniz-Institut für Ostseeforschung Warnemünde
Rutgers-led innovation could spur faster, cheaper, nano-based manufacturing
14.02.2018 | Rutgers University
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
20.04.2018 | Physics and Astronomy
20.04.2018 | Interdisciplinary Research
20.04.2018 | Physics and Astronomy