Derangements in synaptic transmission are part of the pathology of neurological and mental diseases including epilepsy, schizophrenia, depression, and Alzheimer's disease. We are studying the molecular mechanisms underlying regulation of synaptic transmission. In previous years, we have focused on the organization of biochemical regulatory pathways located in the postsynaptic density of glutamatergic synapses. In the previous grant period, we found that RasGAP activity of synGAP, a prominent component of the postsynaptic density and a negative regulator of Ras and Rap signaling, is regulated biphasically by the glutamatergic NMDA receptor (NMDAR), CaMKII, and calcineurin. SynGAP may thus modulate activation of Ras by growth factor receptors at synapses, depending on the timing between activation of the NMDAR and activation of the growth factor receptors. We also found that deletion of synGAP results in increased neuronal apoptosis in brains of mutant mice.
Our Specific Aims i nclude a series of experiments that will test three hypotheses: 1. SynGAP is a key postsynaptic regulator of Ras and Rap at spine synapses; 2. Biphasic regulation of synGAP by the NMDAR, CaMKII, and calcineurin underlies a form of """"""""coincidence detection"""""""" between the NMDAR and other classes of receptors that modulates activation of Ras and/or Rap in the spine; and 3. Derangement of this regulation can shift neuronal biochemical regulatory networks toward initiation of apoptosis. Specifically, we will test; 1) whether activation of NMDARs and synGAP can modulate the level of activation of Ras and ERK by agonists of growth factor receptors including BDNF; and, 2) whether phosphorylation of synGAP by CaMKII changes its RapGAP activity and/or its relative ability to inactivate Ras and Rap. 3) If we find that phosphorylation of synGAP by CaMKII alters its RapGAP activity, we will test whether activation of NMDA receptors in neurons modulates activation of Rap, ERK, and p38 by agonists of receptors that may activate Rap. Finally, 4) We will test the hypothesis that heterozygous and homozygous deletion of synGAP leads to derangements in biochemical pathways that regulate neuronal apoptosis. Alzheimer's disease, and perhaps other neurodegenerative diseases, are believed to begin with relatively subtle dysregulation of synaptic transmission at glutamatergic synapses. Our work may illuminate how synaptic dysregulation can lead eventually to neuronal apoptosis.
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