PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover

Min-Jue Xie; Yasuyuki Ishikawa; Hideshi Yagi; Tokuichi Iguchi; Yuichiro Oka; Kazuki Kuroda; Keiko Iwata; Hiroshi Kiyonari; Shinji Matsuda; Hideo Matsuzaki; Michisuke Yuzaki; Yugo Fukazawa; Makoto Sato

doi:10.1038/s41598-019-40838-6

PIP₃-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover

Sci Rep. 2019 Mar 13;9(1):4305. doi: 10.1038/s41598-019-40838-6.

Authors

Min-Jue Xie^{1

2

3

4

5}, Yasuyuki Ishikawa^{6

7}, Hideshi Yagi^{1

8}, Tokuichi Iguchi^{1

9}, Yuichiro Oka^{1

5

9}, Kazuki Kuroda^{1

2

4}, Keiko Iwata^{3

4

5}, Hiroshi Kiyonari¹⁰, Shinji Matsuda^{11

12

13}, Hideo Matsuzaki^{3

5}, Michisuke Yuzaki¹¹, Yugo Fukazawa^{2

3

4}, Makoto Sato^{14

15

16

17}

Affiliations

¹ Division of Cell Biology and Neuroscience, Department of Morphological and Physiological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.
² Division of Brain Structures and Function, Department of Morphological and Physiological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.
³ Division of Development of Mental Functions, Research Centre for Child Mental Development, University of Fukui, Fukui, 910-1193, Japan.
⁴ Life Science Innovation Centre, University of Fukui, Fukui, 910-1193, Japan.
⁵ United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka University, Osaka, 565-0871, Japan.
⁶ Department of Systems Life Engineering, Maebashi Institute of Technology, Gunma, 371-0816, Japan.
⁷ Laboratory of Functional Neuroscience, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara, 630-0192, Japan.
⁸ Department of Cell Biology, Hyogo College of Medicine, Hyogo, 663-8501, Japan.
⁹ Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
¹⁰ Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, 650-0047, Japan.
¹¹ Department of Neurophysiology School of Medicine, Keio University, Tokyo, 160-8582, Japan.
¹² Department of Engineering Science, Graduate School of Informatics and Engineering, University of Electro-Communications, Tokyo, 182-8585, Japan.
¹³ Japan Science and Technology Agency, PRESTO, Saitama, 332-0012, Japan.
¹⁴ Division of Cell Biology and Neuroscience, Department of Morphological and Physiological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan. makosato@anat2.med.osaka-u.ac.jp.
¹⁵ Division of Development of Mental Functions, Research Centre for Child Mental Development, University of Fukui, Fukui, 910-1193, Japan. makosato@anat2.med.osaka-u.ac.jp.
¹⁶ United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka University, Osaka, 565-0871, Japan. makosato@anat2.med.osaka-u.ac.jp.
¹⁷ Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan. makosato@anat2.med.osaka-u.ac.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Carrier Proteins / metabolism*
Disks Large Homolog 4 Protein / metabolism*
Long-Term Potentiation / physiology*
Membrane Proteins / metabolism*
Memory
Mice
Neuronal Plasticity
Phosphatidylinositol Phosphates / metabolism*
Protein Binding / physiology
Receptors, AMPA / metabolism*
Receptors, N-Methyl-D-Aspartate / metabolism*

Substances

Carrier Proteins
Disks Large Homolog 4 Protein
Membrane Proteins
Phldb2 protein, mouse
Phosphatidylinositol Phosphates
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate
phosphatidylinositol 3-phosphate
Calcium-Calmodulin-Dependent Protein Kinase Type 2