NSF Award
2516603
Everyday activities and behaviors depend on the building of complex brain circuits during development. Critical steps in the maturation of these circuits include neurons extending axons to their correct target, and the formation of synapses, sites of communication between neurons. A family of proteins, membrane receptor tyrosine kinases (RTKs), has well-known roles in neuron growth, target selection and synapse formation. However, the biochemical mechanisms that regulate these proteins action in specific circuits of the developing brain remain unknown. This investigation will determine the impact of dysregulating the function of RTKs in the development of brain circuits that control social and emotional behaviors. The proposed studies will contribute greater insight into circuit maturation during development, that is necessary for basic and complex neural function, such as movement, perception and learning. This research project represents a new collaboration between investigators in Switzerland and the USA, aligning with NSF’s mission to foster and support collaborative international research.<br/><br/>Circuit formation includes axon guidance, target selection and collateralization, and dendritic growth that coincide with synapse formation, maturation and pruning. Receptor tyrosine kinases (RTKs) are a diverse family with well-known roles in these processes. There are significant knowledge gaps in understanding the relation between post-translational modifications of different phosphorylation sites and engagement of select intracellular pathways that mediate diverse neurodevelopmental processes. The MET receptor tyrosine kinase mediates the timing of spine and excitatory synapse maturation in the cortex. A new MET phosphorylation site, serine (S)1014 in mice, was recently discovered and characterized. Mice with a genetic substitution that prevents phosphorylation at that site (METS1014A mice) exhibit neuronal adaptations in the forebrain distinct from those observed following genetic deletion of Met. Studies in the U.S. will determine the profile of S1014 phosphorylation and identify changes in downstream intracellular signaling across cortical development in METS1014A mice. In vitro and in vivo studies will measure the impact of signaling alterations on dendritic growth and synaptogenesis, glutamate synapse maturation and inhibitory neuron development. Studies in Switzerland will determine the role of excitatory-inhibitory imbalance in dysfunctional networks in METS1014A mice. Imaging of neuronal activity and physiological measures of sleep architecture will serve as measures of these signaling adaptations. These studies will contribute to a greater understanding of the potential of altered post-translational RTK signaling to regulate fundamental neurodevelopmental processes that underlie development of circuit-specific complex behavior across species.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
