autism spectrum disorders (ASDs) are a group of prevalent neurodevelopmental disorders that are manifested by devastating cognitive and behavioral dysfunction beginning in early childhood. ASDs have a strong genetic component and have been reported to occur in approximately 20 in 1,000 births in the U.S., and therefore represent a significant health problem, and one that profoundly affects many families in the U.S. military. Currently, no effective cures are available for ASDs, and although some symptoms can be treated with medications, this comes at the cost of significant side effects. However, this panorama may soon change, because research in the field has accelerated and novel laboratory tools have become available to study the fundamental alterations in brain connectivity. One major area of progress in the field of ASD research has been the availability of suitable animal models in which to study how alterations in genes cause disruption in the connectivity and communication of neurons. These advances have enabled us to investigate the root causes of brain circuit dysfunction in experimental models of ASDs, as well as test ways to reverse those abnormalities in an effort to develop innovative drug treatments for individuals suffering from these disorders. Our research has identified two major defects in the brains of mice that are a model of ASD. The first is an abnormality in the synaptic connections between individual brain cells in the cerebral cortex, and the second is a larger-scale defect at the level of brain circuits. We propose that the two defects are linked by a change in an important neurotransmitter called GABA, which has a strong effect on development of the brain. This could explain some of the common symptoms of children with ASDs, including their susceptibility to seizures, their disrupted sleep and anxiety, or the hypersensitivity to touch and other sensation. This matches well a proposed theory for autism in general, known as the Intense World theory, which proposes that autistic children are overwhelmed by every day sensations (visual, tactile, auditory) due to the presence of hyper-excitable brain circuits. Here, we will test the hypothesis that this abnormally high brain activity defect (e.g., the hyper-excitable brain) is caused by defects in the GABA neurotransmitter pathway. We will ask three questions: (1) Is the alteration in GABA signaling present in multiple animal models of ASDs? (2) Is there evidence that similar changes in GABA can exist in human neurons derived from ASD patients? (3) Can we reverse the changes in neuron connectivity and hyper-excitability by using a common drug that enhances GABA's inhibitory function during early development of the brain? Our experimental design will employ cutting-edge techniques to record from brain cells and is designed to incorporate the complementary expertise of three collaborating groups of scientists. Our proposed studies will address important knowledge gaps and potentially provide novel insights into developing cures for ASDs. Because similar abnormalities of neuron connectivity and brain circuits are implicated in other childhood brain disorders, we believe that our unique synapse-to-circuit approach is likely to be of broad importance to many other disorders characterized by autism or intellectual disability.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
