Date of Completion
Met, HGF, Autism, excitatory synapse, neural circuitry, nervous system, NMDA receptors, PSD-95, AMPA receptors.
Field of Study
Physiology and Neurobiology
Doctor of Philosophy
Met is a receptor tyrosine kinase, and activated by its ligand, hepatocyte growth factor (HGF) to regulate a variety of biological activities. In addition to the well-documented implication in carcinogenesis, Met signaling regulates both the structure and the function of the nervous system and serves as a therapeutic target for multiple neural pathologies. In the central nervous system, Met is expressed at the post-synaptic component of excitatory synapses, a unique biochemical and electrical structure termed dendritic spines. There are the expressions of different types of proteins including receptors, ion channels, signaling molecules and scaffolding proteins either on the surface of or within dendritic spines to mediate signals received from upstream neurons. Dendritic spines undergo dynamic changes in both shape and the clustering of synaptic proteins even after maturation, which regulate synaptic plasticity and cognitive functions. Autism spectrum disorders (ASDs) is a group of neurodevelopmental disorders that are defined by the clinical features of unusual stereotypic behaviors, and impaired social and communication skills. Genetic evidence has suggested a close association of ASDs and a single nucleotide polymorphism (rs1858830 C) in the promoter region of MET that attenuates both its transcription efficiency and protein expression. Meanwhile, functional imaging studies have suggested abnormal neural networks that are structurally composed of synapses and dendrites in ASD patients. Furthermore, Met expression spatiotemporally overlaps with synaptogenesis and neurite outgrowth. Thus, it is of great significance to study the influence of impaired signaling by Met and HGF on dendritic spine structure, synaptic clustering of proteins, and dendritic branches for a better understanding of the etiology of ASDs. We present in current study that inhibition of Met signaling causes significant reduction in dendritic spine size and density, clustering of excitatory synaptic proteins, and dendritic arborization of dissociated hippocampal neurons in culture. All of these defects can lead to disrupted organization of neural networks and aberrant information process, which may in turn cause cognitive deficits in ASD individuals with disturbed Met signaling.
Hao, Quanzhen, "Met, an Autism Spectrum Disorder-Associated Protein, Regulates Dendritic Spine Morphology, Clustering of Synaptic Proteins, and Dendritic Arborization of Hippocampal Neurons" (2013). Doctoral Dissertations. 171.