Abstract
The essential involvement of phosphoinositides in synaptic plasticity is well-established, but incomplete knowledge of the downstream molecular entities prevents us from understanding their signalling cascades completely. Here, we determined that Phldb2, of which pleckstrin-homology domain is highly sensitive to PIP3, functions as a phosphoinositide-signalling mediator for synaptic plasticity. BDNF application caused Phldb2 recruitment toward postsynaptic membrane in dendritic spines, whereas PI3K inhibition resulted in its reduced accumulation. Phldb2 bound to postsynaptic scaffolding molecule PSD-95 and was crucial for localization and turnover of PSD-95 in the spine. Phldb2 also bound to GluA1 and GluA2. Phldb2 was indispensable for the interaction between NMDA receptors and CaMKII, and the synaptic density of AMPA receptors. Therefore, PIP3-responsive Phldb2 is pivotal for induction and maintenance of LTP. Memory formation was impaired in our Phldb2−/− mice.
Highlights
Long-lasting changes in the strength of synaptic transmission, such as long-term potentiation (LTP)[1] and long-term depression (LTD)[2], underlies learning and memory
Phldb[2] was observed in the spines of the hippocampal neurons, co-localizing well with the postsynaptic scaffold protein PSD-95 (Supplementary Fig. 1E,F), which is a major component of the postsynaptic density and regulates the maturation of dendritic spines
It has been demonstrated that brain-derived neurotrophic factor (BDNF) acts on the dendritic spines through trkB and is crucial for LTP11–13,21,31
Summary
Long-lasting changes in the strength of synaptic transmission, such as long-term potentiation (LTP)[1] and long-term depression (LTD)[2], underlies learning and memory. High-frequency presynaptic stimulation induces the opening of NMDA receptors and subsequent calcium entry into the cell, leading to LTP induction[5]. Www.nature.com/scientificreports to the long-lasting potentiation of AMPA receptor-mediated excitatory postsynaptic currents (EPSCs). These are underlying molecular machineries for learning and memory[5,6]. After stimulation of the cell by a chemoattractant, phosphatidylinositol 3-kinase (PI3K) is locally activated, resulting in the transient accumulation of PIP3 on the leading edge of directed migrating amoebas and leukocytes[7]. Brain-derived neurotrophic factor (BDNF) and its receptor trkB, for which PIP3 works, have attracted much attention for synaptic plasticity[11,12,13]. We demonstrate that Phldb[2] localizes in the dendritic spines of the hippocampal neurons, functions as a phosphoinositide-responsive entity and plays a pivotal role in synaptic plasticity
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