TrkB and protein kinase Mζ regulate synaptic localization of PSD-95 in developing cortex

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Postsynaptic density 95 (PSD-95) is a key scaffold protein essential for excitatory synapse maturation and learning.
• BDNF/TrkB signaling previously shown to promote synaptic delivery of PSD-95 via vesicular transport.
• PSD-95 palmitoylation is required for its membrane attachment and synaptic insertion.

Purpose of the Study:

• To investigate the role of BDNF/TrkB signaling in PSD-95 palmitoylation and synaptic targeting.
• To identify downstream pathways mediating BDNF-induced PSD-95 palmitoylation and transport.

Main Methods:

• Utilized mouse visual cortical layer 2/3 neurons.
• Investigated BDNF/TrkB signaling, phospholipase Cγ, and protein kinase M ζ (PKMζ) pathways.
• Examined ZDHHC8 phosphorylation and PSD-95 synaptic accumulation in vivo.

Main Results:

• BDNF/TrkB signaling is essential for both PSD-95 palmitoylation and synaptic transport.
• PKMζ signaling, downstream of BDNF/TrkB, regulates ZDHHC8 phosphorylation, a key palmitoylation enzyme.
• PKMζ inhibition reduced synaptic PSD-95 accumulation, which was rescued by ZDHHC8 overexpression.

Conclusions:

• TrkB and PKMζ signaling pathways converge to regulate PSD-95 targeting to synapses.
• Trophic factors like BDNF can regulate protein palmitoylation, a critical post-translational modification.
• Findings offer insights into neurodevelopmental disorders and brain aging.