Non-ionotropic NMDA receptor signaling in structural plasticity of dendritic spines and schizophrenia
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Non-ionotropic NMDA receptor signaling in structural plasticity of dendritic spines and schizophrenia


The crucial ability to remember and learn from past experiences depends on dynamic rewiring of neural circuitry in response to environmental stimuli. This reshaping of synaptic connectivity occurs through a combination of strengthening and weakening of structural units on neuronal branches called dendritic spines where majority of excitatory connections occur. Long-term potentiation (LTP) of synapses allow for strengthening and growth of dendritic spines, whereas long-term depression (LTD) of synapse instead lead to weakening and shrinkage of spines. The molecular signaling pathway that mediates both LTP and LTD associated changes of spine volume is initiated through the activation of N-methyl-d-aspartate receptors (NMDARs). Ion flux through the receptor pore is a crucial factor for induction of LTP and spine growth, whereas emerging studies point to an ion flux-independent signaling of NMDARs in mediating LTD and spine shrinkage. Driven by glutamate binding to the receptor, non-ionotropic NMDAR signaling involves conformational change of the receptor that then requires the activity of p38 MAPK to drive synaptic weakening and shrinkage. Because non-ionotropic NMDAR signaling is activated through glutamate binding to the receptor and results in shrinkage and elimination of dendritic spines, this function of NMDARs may play a role in the development of schizophrenia. Associated with decreased spine density, reduced levels of d-serine, and disinhibition of excitatory synapses, increased binding of glutamate alone would likely activate non-ionotropic NMDAR signaling to promote shrinkage and loss of dendritic spines. Thus, investigation of the molecular pathway of non-ionotropic NMDAR signaling would not only help elucidate the mechanism that drives learning and memory formation, but could also further our understanding of how brain disorders develop. Chapter 1 will be a review of our current understanding of the non-ionotropic NMDAR signaling pathway and its role in structural plasticity of dendritic spines, as well as other processes such as excitotoxicity and endocytosis of NMDARs. As non-ionotropic NMDAR signaling is activated by glutamate binding, Chapter 2 will detail published work in which we identify ion flux-independent signaling of NMDARs to be a crucial part for the induction of LTP associated spine growth. Chapter 3 explores the potential role of non-ionotropic NMDAR signaling in reduced spine density associated with schizophrenia. Here I detail experiments using serine racemase knockout (SRKO) mice to observe changes in structural plasticity of spines and enhanced non-ionotropic NMDAR activation. Chapter 4 will be a reflection on my scientific contribution to the field of structural plasticity, non-ionotropic NMDAR signaling, and schizophrenia. Lastly, the Appendix describes experiments in which a molecule required for non-ionotropic NMDAR signaling is identified, as well as a closer look to if and how dendritic spines or biochemical modifications and interactions are altered in SRKO mice.

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