Different phosphorylation states of CaMKII alpha differentially regulate structural and functional plasticity

Both theoretical and experimental works were conducted on the mechanisms of long-term potentiation (LTP) and long-term depression (LTD), synaptic modifications thought to underlie learning and memory. The goal of the theoretical project was to understand how the tristability (three stable states: basal state, LTP, and LTD) of the synapse is achieved. Achieving tristability has been a mathematical challenge over two decades. This was accomplished by the idea of coupling two bistable molecular switches, based on biochemical properties of protein phosphatase 2A (PP2A) and Ca2+/calmodulin dependent kinase II (CaMKII). The experimental project was aimed to better understand the structural and functional plasticity produced by an intact form of activated CaMKII alpha that is a necessary and sufficient molecule in LTP induction. We transfected hippocampal neurons with a CaMKII alpha mutant form (T286D) that mimics the activation produced by Ca2+-dependent autophosphorylation. Utilizing a new imaging method that I developed and cell-pair recordings from nontransfected and transfected neurons, several findings were made: (1) once autophosphorylated, CaMKII can enhance spine size and density through a nonenzymatic process; (2) enzymatically activated CaMKII bidirectionally potentiates or depresses the AMPAR-mediated synaptic transmission; T286D with phosphorylation at T305/T306 depresses the synaptic strength, whereas T286D with genetic prevention of phosphorylation at T305/T306 (T286D/T305A/T306A) potentiates it; (3) enzymatically activated CaMKII unidirectionally depresses the NMDAR-mediated synaptic transmission; (4) autophosphorylated CaMKII increases spine size regardless of the bidirectional potentiation or depression of synaptic strength, changing the view that spine enlargement and LTP are always associated.