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!
High in calories and low in nutrients when adolescents share pictures of food online
07.04.2016 | University of Gothenburg
Brain connectivity reveals hidden motives
04.03.2016 | Universität Zürich
Using an ultra fast-scanning atomic force microscope, a team of researchers from the University of Basel has filmed “living” nuclear pore complexes at work for the first time. Nuclear pores are molecular machines that control the traffic entering or exiting the cell nucleus. In their article published in Nature Nanotechnology, the researchers explain how the passage of unwanted molecules is prevented by rapidly moving molecular “tentacles” inside the pore.
Using high-speed AFM, Roderick Lim, Argovia Professor at the Biozentrum and the Swiss Nanoscience Institute of the University of Basel, has not only directly...
If a person pushes a broken-down car alone, there is a certain effect. If another person helps, the result is the sum of their efforts. If two micro-particles are pushing another microparticle, however, the resulting effect may not necessarily be the sum their efforts. A recent study published in Nature Communications, measured this odd effect that scientists call “many body.”
In the microscopic world, where the modern miniaturized machines at the new frontiers of technology operate, as long as we are in the presence of two...
Researchers from the Max Planck Institute Stuttgart have developed self-propelled tiny ‘microbots’ that can remove lead or organic pollution from contaminated water.
Working with colleagues in Barcelona and Singapore, Samuel Sánchez’s group used graphene oxide to make their microscale motors, which are able to adsorb lead...
Neutron scattering and computational modeling have revealed unique and unexpected behavior of water molecules under extreme confinement that is unmatched by any known gas, liquid or solid states.
In a paper published in Physical Review Letters, researchers at the Department of Energy's Oak Ridge National Laboratory describe a new tunneling state of...
Honeycomb structures as the basic building block for industrial applications presented using holo pyramid
Researchers of the Alfred Wegener Institute (AWI) will introduce their latest developments in the field of bionic lightweight design at Hannover Messe from 25...
27.04.2016 | Event News
15.04.2016 | Event News
12.04.2016 | Event News
03.05.2016 | Physics and Astronomy
03.05.2016 | Life Sciences
03.05.2016 | Physics and Astronomy