title: TrkB and protein kinase Mζ regulate synaptic localization of PSD-95 in developing cortex.
abstract: Postsynaptic density 95 (PSD-95), the major scaffold at excitatory synapses, is critical for synapse maturation and learning. In rodents, eye opening, the onset of pattern vision, triggers a rapid movement of PSD-95 from visual neuron somata to synapses. We showed previously that the PI3 kinase-Akt pathway downstream of BDNF/TrkB signaling stimulates synaptic delivery of PSD-95 via vesicular transport. However, vesicular transport requires PSD-95 palmitoylation to attach it to a lipid membrane. Also, PSD-95 insertion at synapses is known to require this lipid modification. Here, we show that BDNF/TrkB signaling is also necessary for PSD-95 palmitoylation and its transport to synapses in mouse visual cortical layer 2/3 neurons. However, palmitoylation of PSD-95 requires the activation of another pathway downstream of BDNF/TrkB, namely, signaling through phospholipase Cγ and the brain-specific PKC variant protein kinase M ζ (PKMζ). We find that PKMζ selectively regulates phosphorylation of the palmitoylation enzyme ZDHHC8. Inhibition of PKMζ results in a reduction of synaptic PSD-95 accumulation in vivo, which can be rescued by overexpressing ZDHHC8. Therefore, TrkB and PKMζ, two critical regulators of synaptic plasticity, facilitate PSD-95 targeting to synapses. These results also indicate that palmitoylation can be regulated by a trophic factor. Our findings have implications for neurodevelopmental disorders as well as aging brains.
authors.affiliation: Departmens of Brain and Cognitive Science, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ayoshii@mit.edu
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshii
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Murata
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Martha
authors.initials: M
authors.lastname: Constantine-Paton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D016503:Drug Delivery Systems; D005260:Female; D051528:Guanylate Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D020813:Receptor, trkB / Q000502:physiology*; D013569:Synapses / Q000737:chemistry / Q000378:metabolism*; D014793:Visual Cortex / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins; D011493:Protein Kinase C; D020813:Receptor, trkB; D000099221:Protein Kinase C zeta; C501447:Dlg4 protein, mouse