Role of CNTNAP2 in neuronal structural development and synaptic transmission
Meixner Translational Postdoctoral Fellowship
Dysfunction in the gene expressing contactin-associated protein-2 (CNTNAP2 or CASPR2) has been linked to a range of developmental neuropsychiatric conditions including autism spectrum disorders (ASDs), epilepsy, Tourette syndrome, schizophrenia, ADHD, and learning disability. Yet despite its obvious importance to human health, our understanding of its molecular function in neurons is poorly understood. Preliminary data suggests that CNTNAP2 dysfunction leads to a deficit in neuronal dendritic and spine structural development, resulting in abnormal synaptic transmission as a result. This study expands upon this initial finding by thoroughly evaluating CNTNAP2 function in governing neuronal development and synaptic transmission using morphological and electrophysiological assays routinely applied in the mentors’ labs. Specifically, the study analyzes CNTNAP2 macromolecular complex components that have been previously implicated in dendritic guidance and growth for their respective contributions to CNTNAP2 function in controlling neuron development. Further investigated is the role of CNTNAP2 function governing neuronal development versus its function in mature neurons by performing in vivo manipulations of CNTNAP2. Using the well-characterized circuit of the CA3-CA1 Schaffer collateral synapse as a model, the researchers include in vivo manipulations of CNTNAP2 both in juvenile and in adult mice, and characterize alterations in neuronal morphology and AMPA- and NMDA-receptor mediated synaptic responses at excitatory synapses onto CA1 pyramidal cells. The goal of this study is to increase the fundamental understanding of CNTNAP2 and the macromolecular complexes that it interacts with, and provide insight into the neuronal pathways that are affected by CNTNAP2 dysfunction in both developing and mature neurons in vivo. This work has the potential to pave the way towards supplying the necessary tools and strategies to one day treat autistic patients with CNTNAP2 genetic dysfunction, and further to provide a model platform towards our understanding of other genes that have also been implicated in the development of ASDs.