This proposal addresses the structure-function relationship of synaptic junction: the molecular mechanisms of neurotransmitter release and morphological synaptic plasticity, and how these two processes are linked to each other. The long-term objective is to delineate the basic principles governing the stability of synaptic connectivity in central neurons, and the significance of these mechanisms to information storage and brain dysfunction underlying mental illnesses. Electrophysiological and imaging methods will be applied in dissociated hippocampal neurons grown in culture to investigate how actin-binding proteins and regulators of actin dynamics modulate release-ready synaptic vesicles, and how changes in synaptic activity, in turn, regulate presynaptic morphology.
Three specific aims of the application are: (I) How do modulators of actin dynamics regulate synaptic vesicle exocytosis? We will characterize the role of modulators of actin dynamics in regulating synaptic vesicle cycle. Our working model is that modulators of actin dynamics act during vesicle docking and/or priming step to regulate the probability of neurotransmitter release. (II) How do synaptic cell adhesion molecules regulate neurotransmitter release? Contribution of the components of cell adhesion complex - integrin, cadherin and beta-catenin -in regulating synaptic vesicle exocytosis will be examined. We will test the hypothesis that cell adhesion molecules regulate synaptic transmission by modifying the dynamics of actin cytoskeleton to which they are linked intracellularly. (III) How is neuronal activity transduced to elicit changes in presynaptic morphology? We will address whether actin modulators and components of cell adhesion proteins studied in Aims I and II mediate activity-induced morphological plasticity of presynaptic actin, specifically, its redistribution to create new presynaptic structures. Our hypothesis is that synaptic cell adhesion molecules act as a signaling mechanism that transduces electrical signal into a morphological change by regulating actin dynamics.
| Cingolani, Lorenzo A; Thalhammer, Agnes; Yu, Lily M Y et al. (2008) Activity-dependent regulation of synaptic AMPA receptor composition and abundance by beta3 integrins. Neuron 58:749-62 |
| Okuda, Takashi; Yu, Lily M Y; Cingolani, Lorenzo A et al. (2007) beta-Catenin regulates excitatory postsynaptic strength at hippocampal synapses. Proc Natl Acad Sci U S A 104:13479-84 |
| Tokuoka, Hirofumi; Goda, Yukiko (2006) Myosin light chain kinase is not a regulator of synaptic vesicle trafficking during repetitive exocytosis in cultured hippocampal neurons. J Neurosci 26:11606-14 |
