PTEN dampens PIP3 upregulation in spines during NMDA receptor-dependent long-term depression

Abstract

PI3K and PTEN have been shown to participate in synaptic plasticity, during long-term potentiation (LTP) and long-term depression (LTD), respectively. Nevertheless, the dynamics of phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) and the regulation of its synthesis and degradation at synaptic compartments is far from clear. Here, we have used FRET imaging to monitor changes in PIP3 levels in dendritic spines from CA1 hippocampal neurons under basal conditions and upon induction of NMDA receptor-dependent LTD and LTP. We found that PIP3 is under constant turnover in dendritic spines. Contrary to the expectation, both LTD and LTP induction trigger an increase in PIP3 synthesis, which requires NMDA receptors and PI3K activity. Using biochemical methods, the upregulation of PIP3 levels during LTP was estimated to be two-fold. However, in the case of LTD, PTEN activity counteracts the increase in PIP3 synthesis, resulting in no net change in PIP3 levels. Therefore, both LTP and LTD signaling converge towards PIP3 upregulation, but PTEN acts as an LTD-selective switch that determines the outcome of PIP3 accumulation.