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Pat Levitt, Ph.D., Published in Neurosciences Journal

October 14, 2007

Pat Levitt, Ph.D., the chair of Cure Autism Now's Scientific Advisory Board co-authored a research review published in the July, 2004, issue of Trends in Neurosciences regarding the involvement of interneuron regulation in neurodevelopmental disorders such as autism.

Interneurons form prenatally and early after birth. These neurons help to mediate communication throughout the brain. The proporation of interneurons which dampen or amplify nerve signaling is critical to brain development and is relatively well shared among mammals. Interneurons which tend to dampen nerve signaling secrete a chemical called GABA. GABA secreting interneurons have a very sophisticated and delicate developmental program mediated by a set of signaling molecules that attract or repel the growth and movement of these neurons into particular areas of the developing brain.

Recent studies into the development of these interneuron circuits have identified a set of genes and biological pathways which, when disrupted, share some biophysical and biobehavioral aspects with autism and schizophrenia. An unexpected finding showed that a protein originally involved in the expansion of cells in the liver (Hepatocyte Growth Factor, HGF), was important for the movement of nerve cells to their correct location in the brain network.

Due to the fact that this protein is critical for the liver and lungs, as well as the development of interneurons, mice which lacked the HGF gene died prenatally before interneuron development could be observed. However, another protein (urokinase plasminogen activator, uPA) is responsible for activating HGF. While uPA activates HGF on its own, a third protein called uPAR (urokinase plasminogen activator receptor) significantly enhances how efficiently that activation happens. By eliminating the uPAR gene from mice, scientists were able to observe some behavioral changes reminiscent of autism.

Mice lacking uPAR had an increased susceptibility to seizure, an altered EEG profile, increased anxiety-like behavior and significant social interaction. Many of these features are shared with individuals with autism. For example, it has been reported that 15-30% of children with autism in a particular study had seizure activity. Furthermore, most individuals with autism display an altered EEG profile and often show abnormalities in sleep-wake cycles, indicative in problems with the amplification or dampening of the nervous system.

This review article highlighted particular literature and proposed models by which autism may develop due to deficiencies in interneuron development. This model will be examined experimentally and tested scientifically in the months and years to come.