Protein phosphatase 1 isoforms, human de novo mutations and synaptic functions

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Reversible phosphorylation is a critical regulatory mechanism for spine morphogenesis, synaptic transmission, long-term potentiation (LTP) and memory formation. Protein phosphatase 1 (PP1) contributes to almost half of the serine/threonine phosphorylation in the mammalian cells, however, the role of three different PP1 isoforms (PP1α, β, γ) in these processes is ill defined. PP1β is not believed to play a role in CNS function. On the other hand, whether PP1α and PP1γ play a role in synaptic functions have never been determined directly. By using conditional knockout mouse models, we found that PP1β inhibits synaptic transmission and spine maturation while promotes LTP induction and memory formation. On the other hand, we found that PP1γ increases synaptic transmission, with PP1α compensating PP1γ. The overarching hypothesis of this application is that myosin phosphatase targeting 1 (MYPT1) and neurabin (Nrb) mediate the distinct effects of PP1β and PP1γ/α on synaptic function, respectively. In detail, we will test our hypothesis in Aim 1 that PP1β-MYPT1 holoenzyme inhibits non-muscle myosin IIB-mediated F-actin contraction in inhibiting spine maturation and synaptic transmission. We will determine in Aim 2 that PP1γ, in combination with PP1α, promotes spine maturation, synaptic transmission by interaction with Nrb, a major synaptic scaffolding protein. We will also test our prediction that PP1γ/α achieves these via dephosphorylating Nrb at Ser200. In Aim 3 we will test our prediction that PP1β inhibits LTD induction, promotes LTP induction and memory formation while PP1γ/α plays an opposite role. We will determine the structure-synaptic function relationship in the roles of PP1β in synaptic transmission and plasticity, with an emphasis on PP1β C-termini in which one of the human PP1β de novo mutations resides. These studies will provide signaling mechanisms of, and structure determinants on, PP1 isoforms in regulating their distinct roles on synaptic functions.