PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover
PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover
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DOI：
10.1038/s41598-019-40838-6
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发表时间：
2019-03
影响因子：
4.6
通讯作者：
Min-jue Xie;Yasuyuki Ishikawa;H. Yagi;Tokuichi Iguchi;Yuichiro Oka;K. Kuroda;Keiko Iwata;H. Kiyonari;S. Matsuda;Hideo Matsuzaki;M. Yuzaki;Y. Fukazawa;Makoto Sato
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文献类型：
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作者：
Min-jue Xie;Yasuyuki Ishikawa;H. Yagi;Tokuichi Iguchi;Yuichiro Oka;K. Kuroda;Keiko Iwata;H. Kiyonari;S. Matsuda;Hideo Matsuzaki;M. Yuzaki;Y. Fukazawa;Makoto Sato
肌醇磷脂在突触可塑性中的重要作用是公认的，但对下游分子实体的不完全了解阻碍了我们完全理解它们的信号级联反应。在这里，我们确定了Phld2，其pleckstrin同源结构域对PIP3高度敏感，作为突触可塑性的磷脂酰肌醇信号媒介发挥作用。应用BDNF可使PhldB2向树突棘突触后膜募集，而抑制PI3K可使其积聚减少。Phldb2与突触后支架分子PSD-95结合，对PSD-95在脊髓中的定位和周转起关键作用。PhlDB2还与GluA1和GluA2结合。在NMDA受体与CaMKII的相互作用和AMPA受体的突触密度中，Phld2是必不可少的。因此，PIP3应答的Phldb2在LTP的诱导和维持中起着关键作用。我们的Phldb2−/−小鼠的记忆形成受到了损害。
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 ourPhldb2−/−mice.