Novel roles of striatal enriched protein phosphatase (STEP) in neuronal intrinsic properties and homeostatic synaptic plasticity
STriatal Enrich Protein Phosphatase (STEP) is a brain specific protein tyrosine phosphatase, which is only expressed in the central nervous system (CNS). STEP has two major isoforms, including STEP46 and STEP61 and membrane-bound STEP61 is implicated in multiple neurologic disorders. For example, the level of STEP61 is elevated in animal disease models and postmortem samples of Alzheimer’s disease and Schizophrenia, whereas its activity is reduced in brain ischemia and Huntington’s diseases. STEP61 regulates Hebbian forms of synaptic plasticity, which has been considered as a mechanism by which the information is encoded and stored at the synapse. STEP61 is involved in the internalization of the N-methyl-D-aspartate receptors (NMDARs) and the α-amino-hydroxy-5-methyl-4-isoxazolepropinoic acid receptors (AMPARs) via dephosphorylating Tyr1472 of GluN2B subunit in NMDAR and 3 Tyr (Tyr869, Tyr873, and Tyr876) of GluA2 subunit in AMPAR. Despite extensive studies on the role of STEP61 in activity-dependent synaptic plasticity, including long-term synaptic potentiation and depression, it was unknown whether STEP contributes to homeostatic synaptic plasticity, a compensatory mechanism by which neurons adjust their synaptic strength within a normal range in response to chronic activity challenge. In addition, whether STEP regulates somatic intrinsic properties of hippocampal pyramidal neurons has to be addressed. This dissertation is focused on finding novel roles of STEP in homeostatic adjustment of synaptic strength and neuronal intrinsic properties in the hippocampus. The first chapter of this work describes background information about keywords related to research topics written in this dissertation. In the second chapter, I describe the results on the involvement of STEP in homeostatic synaptic plasticity using in vitro primary hippocampal cultured neurons. In the third and fourth chapter, I describe the alteration of STEP expression and activity and the elevation of amyloid-β following an electroconvulsive seizure (ECS) and Kainic-acid (KA) induced status epilepticus (SE) accompanied by network hyper-excitability. The fifth chapter provides a novel evidence into STEP regulates neuronal intrinsic properties in the hippocampal neurons. In the part of appendix, I describe subcellular fractionation technique using hippocampi from rats which underwent ECS, and molecular and electrophysiological verification of chemical long-term potentiation (cLTP). Taken together, the findings in this dissertation suggest that STEP plays crucial roles in mediating homeostatic responses at the excitatory synapses and regulating intrinsic neuronal properties of hippocampal pyramidal neurons.
Striatal Enriched Protein Phosphatase NEURONAL PROPERTIES
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign