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

ABSTRACT Phosphoinositide 3-kinase (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 (PIP 3 ) and the regulation of its synthesis and degradation at synaptic compartments is far from clear. Here, we have used fluorescence resonance energy transfer (FRET) imaging to monitor changes in PIP 3 levels in dendritic spines from CA1 hippocampal neurons under basal conditions and upon induction of NMDA receptor (NMDAR)-dependent LTD and LTP. We found that PIP 3 undergoes constant turnover in dendritic spines. Contrary to expectations, both LTD and LTP induction trigger an increase in PIP 3 synthesis, which requires NMDARs and PI3K activity. Using biochemical methods, the upregulation of PIP 3 levels during LTP was estimated to be twofold. However, in the case of LTD, PTEN activity counteracts the increase in PIP 3 synthesis, resulting in no net change in PIP 3 levels. Therefore, both LTP and LTD signaling converge towards PIP 3 upregulation, but PTEN acts as an LTD-selective switch that determines the outcome of PIP 3 accumulation.