Regulation of Dendritic Spine Morphology in Hippocampal Neurons by Copine-6

• Published in: Cerebral cortex (New York, N.Y. 1991) N.Y. 1991), 2018-04, Vol.28 (4), p.1087-1104
• Main Authors: Burk, Katja, Ramachandran, Binu, Ahmed, Saheeb, Hurtado-Zavala, Joaquin I, Awasthi, Ankit, Benito, Eva, Faram, Ruth, Ahmad, Hamid, Swaminathan, Aarti, McIlhinney, Jeffrey, Fischer, Andre, Perestenko, Pavel, Dean, Camin
• Format: Article
• Language: English
• Subjects: Animals; Brain-Derived Neurotrophic Factor - pharmacology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Dendritic Spines - physiology; Dendritic Spines - ultrastructure; Disks Large Homolog 4 Protein - metabolism; Hippocampus - cytology; Humans; Mice; Microtubule-Associated Proteins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - physiology; Neurons - ultrastructure; Organ Culture Techniques; Rats; Receptor, trkB - genetics; Receptor, trkB - metabolism; Synapses - drug effects; Synapses - physiology; Synapses - ultrastructure; Synaptic Potentials - drug effects; Synaptic Potentials - genetics; Synaptic Vesicles - drug effects; Synaptic Vesicles - physiology; Synaptosomes - metabolism; Synaptosomes - ultrastructure; Vesicular Glutamate Transport Protein 1 - metabolism; Vesicular Inhibitory Amino Acid Transport Proteins - metabolism
• ISSN: 1047-3211; 1460-2199
• DOI: 10.1093/cercor/bhx009

Abstract Dendritic spines compartmentalize information in the brain, and their morphological characteristics are thought to underly synaptic plasticity. Here we identify copine-6 as a novel modulator of dendritic spine morphology. We found that brain-derived neurotrophic factor (BDNF) - a molecule essential for long-term potentiation of synaptic strength - upregulated and recruited copine-6 to dendritic spines in hippocampal neurons. Overexpression of copine-6 increased mushroom spine number and decreased filopodia number, while copine-6 knockdown had the opposite effect and dramatically increased the number of filopodia, which lacked PSD95. Functionally, manipulation of post-synaptic copine-6 levels affected miniature excitatory post-synaptic current (mEPSC) kinetics and evoked synaptic vesicle recycling in contacting boutons, and post-synaptic knockdown of copine-6 reduced hippocampal LTP and increased LTD. Mechanistically, copine-6 promotes BDNF-TrkB signaling and recycling of activated TrkB receptors back to the plasma membrane surface, and is necessary for BDNF-induced increases in mushroom spines in hippocampal neurons. Thus copine-6 regulates BDNF-dependent changes in dendritic spine morphology to promote synaptic plasticity.