The activation of NMDAR by patterns of synaptic activity during long-term potentiation (LTP) is thought to regulate a number of protein kinases that potentiate synaptic transmission by phosphorylating proteins within the postsynaptic density (PSD). At the PSD of excitatory glutamatergic synapse, these phosphorylated proteins are thought to associate in protein interaction networks. These networks can convey important mechanism for processing, integrating and storing information at synapses in health and disease states. However, only a small number of phosphorylation sites are known. Moreover, there is no information on how NMDAR dependent high frequency stimulation-LTP modulates protein phosphorylation networks in temporal health and disease states. Our primary objectives here are to determine the temporal and NMDAR dependent phosphorylation networks triggered by the induction of LTP, and identify how synaptic stimulation in the presence of ?-adrenergic receptor agonists regulates patterns of synaptic activity and protein interactions in the PSD, of both wild type and SynGAP mutant mice, a mouse model of intellectual disability. For this purpose we will use a combination of mouse hippocampus CA1 mini-slices, mass spectrometry, bioinformatics and mouse genetics. This will allow a better understanding of the role of the SynGAP mutation in the composition of PSD networks and the convergence of NMDAR and ?-adrenergic receptors in LTP signaling networks and will inform future studies to be able to manipulate and regulate PSD signaling.
Although a small number of proteins within the postsynaptic density (PSD) of excitatory synapses are known to be phosphorylated following LTP induction, the PSD is composed of more than 1,500 proteins that contain 100's of phosphorylation sites. The proposed research will increase our understanding of the molecular changes that are regulated by LTP, and how they are modulated by mutations associated to intellectual disability. This will allow the identification of novel proteins and signaling processes involved in synaptic plasticity, ID, and neuromodulation that will facilitate the development of future, hypothesis driven experiments.
| Wilkinson, Brent; Evgrafov, Oleg V; Zheng, DongQing et al. (2018) Endogenous Cell Type-Specific Disrupted in Schizophrenia 1 Interactomes Reveal Protein Networks Associated With Neurodevelopmental Disorders. Biol Psychiatry : |
