Synaptic Accumulation of PSD-95 and Synaptic Function Regulated by Phosphorylation of Serine-295 of PSD-95

• Published in: Neuron (Cambridge, Mass.) Vol. 56; no. 3; pp. 488 - 502
• Main Authors: Kim, Myung Jong, Futai, Kensuke, Jo, Jihoon, Hayashi, Yasunori, Cho, Kwangwook, Sheng, Morgan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.11.2007; Elsevier Limited
• Subjects: Animals; Animals, Newborn; CELLBIO; Cells, Cultured; Deoxyribonucleic acid; Disks Large Homolog 4 Protein; DNA; Excitatory Amino Acid Agonists - pharmacology; Excitatory Postsynaptic Potentials - physiology; Experiments; Hippocampus - metabolism; Hippocampus - ultrastructure; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - physiology; Medical research; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; MOLNEURO; Mutation - physiology; N-Methylaspartate - pharmacology; Neurons; Organ Culture Techniques; Phosphorylation; Phosphorylation - drug effects; Proteins; rac1 GTP-Binding Protein - metabolism; Rats; Receptors, AMPA - drug effects; Receptors, AMPA - metabolism; Serine - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Studies; Synaptic Membranes - drug effects; Synaptic Membranes - metabolism; Synaptic Membranes - ultrastructure; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; CELLBIO; MOLNEURO
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2007.09.007

The scaffold protein PSD-95 promotes the maturation and strengthening of excitatory synapses, functions that require proper localization of PSD-95 in the postsynaptic density (PSD). Here we report that phosphorylation of ser-295 enhances the synaptic accumulation of PSD-95 and the ability of PSD-95 to recruit surface AMPA receptors and potentiate excitatory postsynaptic currents. We present evidence that a Rac1-JNK1 signaling pathway mediates ser-295 phosphorylation and regulates synaptic content of PSD-95. Ser-295 phosphorylation is suppressed by chronic elevation, and increased by chronic silencing, of synaptic activity. Rapid dephosphorylation of ser-295 occurs in response to NMDA treatment that causes chemical long-term depression (LTD). Overexpression of a phosphomimicking mutant (S295D) of PSD-95 inhibited NMDA-induced AMPA receptor internalization and blocked the induction of LTD. The data suggest that synaptic strength can be regulated by phosphorylation-dephosphorylation of ser-295 of PSD-95 and that synaptic depression requires the dephosphorylation of ser-295.