Long-term synaptic depression (LTD) and depotentiation, the two forms of sustained synaptic depression after periods of repetitive synaptic activity, are extensively studied examples of vertebrate synaptic plasticity. The cellular and molecular mechanisms responsible for LTD and depotentiation will likely elucidate physiological and pathological phenomena of neural development, adaptation, learning and memory. There is now compelling evidence that repetitive synaptic activity leads to activation of NMDA-sensitive glutamate receptors (NMDA-Rs) and removal of postsynaptic AMPA-sensitive glutamate receptors (AMPA-Rs) from excitatory synapses during LTD and depotentiation. However, the biochemical pathways that link NMDA-R activity to AMPA-R trafficking are largely unknown. We have previously reported that small GTPase Rap1 controls LTD via activation of p38MAPK. In a preliminary study, we observed that small GTPase Rap2 controls depotentiation via activation of JNK. Based on these findings, I proposed a new model that Rap1 and Rap2 signal synaptic depression via two independent signaling pathways. We will test three hypotheses in this model with three aims, respectively, using an organotypic culture hippocampal slice preparation. This preparation allows us to manipulate synaptic activity and signaling molecules' activity using physiology, pharmacology and recombinant protein delivery methods. We will assay the effects of these manipulations by examining electrophysiologically tagged recombinant AMPA-R-mediated currents, measuring synaptic responses in GluR1 and GluR2 knockout mice, as well as quantifying phosphorylated or active endogenous signaling molecules and glutamate receptors. Combining these approaches, we will determine whether:
(Aim 1) Rap1-p38MAPK signals LTD whereas Rap2-JNK signals depotentiation;
(Aim 2) different downstream signaling molecules relay Rap1-p38MAPK and Rap2-JNK pathways;
and (Aim 3) different upstream signaling molecules control Rap1-p38MAPK and Rap2-JNK pathways. Because genetic defects in signaling molecules or enzymes controlling Rap signaling pathways lead to severe mental retardation, the findings from this study should also suggest additional molecular targets for novel genetic and pharmacological strategies that may efficaciously treat these insidious mental diseases. ? ? ?
| Zhang, Lei; Zhang, Peng; Wang, Guangfu et al. (2018) Ras and Rap Signal Bidirectional Synaptic Plasticity via Distinct Subcellular Microdomains. Neuron 98:783-800.e4 |
| Stornetta, Ruth L; Zhu, J Julius (2011) Ras and Rap signaling in synaptic plasticity and mental disorders. Neuroscientist 17:54-78 |
| Kielland, Anders; Bochorishvili, Genrieta; Corson, James et al. (2009) Activity patterns govern synapse-specific AMPA receptor trafficking between deliverable and synaptic pools. Neuron 62:84-101 |
| Zhu, J Julius (2009) Activity level-dependent synapse-specific AMPA receptor trafficking regulates transmission kinetics. J Neurosci 29:6320-35 |
| Ouyang, Ming; Zhang, Lei; Zhu, J Julius et al. (2008) Epac signaling is required for hippocampus-dependent memory retrieval. Proc Natl Acad Sci U S A 105:11993-7 |
| Hu, Hailan; Qin, Yi; Bochorishvili, Genrieta et al. (2008) Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome. J Neurosci 28:7847-62 |
