Autism as a Synaptopathy
Autism or Autism Spectrum Disorders (ASD) now affect 1 in 88 individuals in the US. It is primarily a disorder that affects social interaction and communication (more here). Over the past 10 years, research has made significant progress in localizing the alterations at the root of ASD at the molecular and cellular level. In 2003, Dr. Huda Zoghbi first categorized neurodevelopmental disorders, such as ASD, as being disorders of the development and function of synapses (Zoghbi, 2003). Synapses are the main sites of communication between neurons, and are critical for the brain to function (more here) . The main piece of evidence to suggest that a synaptopathy (or pathology of the synapse; Brose et al., 2010; Grant, 2012) might underlie ASD came in the form of genetic studies demonstrating mutations in the neuroligin genes in individuals with autism and Asperger Syndrome (Jamain et al., 2003). A significant amount of work had previously shown that the molecules encoded by the neuroligin genes localize to synapses and aid in their development and maturation (Scheiffele et al., 2000).
Since these first inklings into the molecular causes of ASD, much work has gone into identifying additional ASD genes, and into characterizing the molecular, cellular and behavioral deficits caused by mutations in known ASD genes. Now, over 30 genes have been identified with mutations associated with ASDs (Aldinger et al., 2011). A core of these genes encodes proteins that either localize to and function at synapses, or that regulate synaptic function. Examples include the cell adhesion molecules neuroligins and their adhesive partners, neurexins, also their intracellular binding partners, shanks (Grant, 2012). Studies of mouse models with mutations in these genes point towards deficits at synapses that use the neurotransmitter glutamate (Auerbach et al., 2011; Baudouin et al., 2012; Blundell et al., 2010; Hoy et al., 2013; Won et al., 2012). Since glutamate receptors, such as the NMDA and metobotropic glutamate receptors, are easy targets for pharmaceutical approaches, it is now a hope that researchers are close to developing drug therapies for autism (Spooren et al., 2012).
In the Washbourne Lab, our research focuses on how glutamatergic synapses form and what deficits arise in the absence of key ASD genes. We are also planning experiments to evaluate the possibility of using zebrafish with mutations in ASD genes with which to screen for potential drug candidates (for more on this project click here).