NAAR-funded researcher Dr. Peter Scheiffele, of Columbia University's Center for Neurobiology and Behavior, has recently co-authored a study focusing on neuronal circuitry and the development of autism.
The study, "Disorder-Associated Mutations Lead to Functional Inactivation of Neuroligins," was recently published in the online version of Human Molecular Genetics. The study suggests that previously identified mutations in neuroligin genes are likely to be relevant for neurodevelopmental defects in autism spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule.
In 2003, Dr. Scheiffele was awarded a two-year $119,998 grant for his pilot study, Frequency and Functional Characterization of Neuroligin Mutations.
"The research support from NAAR allowed us to investigate directly how mutations in neuroligin genes might affect the function of neuroligin proteins during the development of the nervous system," said Dr. Scheiffele. "We are extremely grateful for the support from NAAR that made this work possible."
It has been proposed that alterations in neuronal circuitry are responsible for the development of autistic disorders. However, the cellular basis of such alterations is unknown.
Dr. Scheiffele's laboratory has studied the molecular mechanisms of neuronal circuit formation during normal development of the brain. In these studies, Dr. Scheiffele and his team have discovered that a family of neuronal receptors called neuroligins has an activity that promotes the formation of connections between nerve cells. Last year, a human genetics study carried out by another research group identified mutations in these neuroligin proteins in patients with autism-spectrum disorders.
In collaboration with Dr. Lorraine Clark, a human geneticist at Columbia University, Dr. Scheiffele's team observed that the mutated neuroligin proteins that are found in patients with autism spectrum disorders loose their ability to stimulate the formation of neuronal connections.
"Our findings provide a cellular basis for the neurodevelopmental defects in autistic patients and highlight the relevance of perturbed neuronal connectivity for this disorder," said Dr. Scheiffele.
Dr. Scheiffele added that further work elucidating how circuit formation is controlled during normal brain development, especially with respect to the function of the neuroligin proteins, should therefore lead to strategies to restore normal neuronal connectivity and to reduce the neurodevelopmental defects in autism spectrum disorders in the future.
Below is the abstract of the study published in Human Molecular Genetics.
DISORDER-ASSOCIATED MUTATIONS LEAD TO FUNCTIONAL INACTIVATION OF NEUROLIGINS
Ben Chih, Shehla Khan Afridi, Lorraine Clark, Peter Scheiffele
Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, NY (Chih and Sceiffele) Taub Institute, Department of Pathology, Columbia University, New York, NY (Afridi and Clark)
Autism is a neuro-developmental syndrome that affects 0.1-0.5% of the population. It has been proposed that alterations in neuronal circuitry and/or neuronal signaling are responsible for the behavioral and cognitive aberrations in autism patients. However, the cellular basis of such alterations is unknown. Recently, point mutations in a family of neuronal cell adhesion molecules called neuroligins have been linked to autism-spectrum disorders and mental retardation. We investigated the consequences of these disease-associated mutations on neuroligin function. We demonstrate that the point mutation in arginine 451 and a nonsense mutation at aspartate 396 of neuroligin-3 and -4, respectively, result in intracellular retention of the mutant proteins.
Over-expression of wild-type neuroligin-3 and -4 proteins in hippocampal neurons stimulates the formation of presynaptic terminals whereas the disease-associated mutations result in a loss of this synaptic function.
Our findings suggest that the previously identified mutations in neuroligin genes are likely to be relevant for the neurodevelopmental defects in autism-spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule.