Jyothi Arikkath, Ph.D. - US grants

Project Summary: Autism is a debilitating neurodevelopmental disorder associated with social and cognitive deficits. Autism compromises the quality of life of affected individuals and place an enormous financial and emotional burden on families and the healthcare system. Advances that promote novel therapeutic approaches are thus a critical need. Mutations in CTNND2, encoding ?-catenin, have been identified in autism. However, the normal functional roles of ?-catenin and how autism mutations perturb this functional role remain unclear. We have identified critical roles for ?-catenin in regulating dendrites, spines and transcription. Based on our preliminary data, we propose that ?-catenin interacts with specific interactors in different cellular compartments to function in these diverse signaling pathways. Further, we propose that autism mutations perturb these interactions or ability to function in these signaling pathways, thus compromising neural circuit formation and contributing to the phenotype of autism. In this proposal, we propose to take advantage of an affinity purification technique to identify and characterize compartment specific binding partners of ?-catenin from the mouse hippocampus. We expect that these studies will aid in further defining the functional roles of ??catenin and delineate the signaling pathways that are aberrant in autism associated with mutations in CTNND2. Thus these studies will eventually aid the development of novel therapeutic approaches for this devastating disorder.

Synaptic aberrations are commonly observed in a wide variety of neurodevelopmental disorders associated with autism, epilepsy, intellectual disability and related phenotypes. While synaptic proteomic aberrations have been identified in several models of neurodevelopmental disorders, these studies are mainly performed from whole tissue samples and few provide data on synaptic alterations in a neuron-type or synapse-type specific manner. Thus, synaptic alterations that are confined to specific types of synapses or neurons might be poorly detected using this approach due to lack of technical sensitivity. The availability of a validated technique to allow the detection of synaptic alterations in mouse models of human disorders in a neuron-type and synapse-type specific manner would accelerate our therapeutic efforts for disorders associated with synaptic aberrations. In this discovery and validation proposal, we propose to mouse models of a neurodevelopmental disorder, with known differential alterations in synaptic proteins in excitatory and inhibitory neurons, to define and validate proteomic compositions of excitatory synaptosomes in a neuron type specific manner. The success of our studies will allow great insights into the synaptic pathology neurodevelopmental disorders with synaptic aberrations. The tools, techniques and approach can be applied more globally, thus promoting great strides in cellular and molecular neuroscience.