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BDNF-enhancer drug facilitates learning in Angelman mice

Speaker: John Marshall

Report time: Jan.5, 2018, 10:00

Report location: 401-1500, Meeting Room, Institute of Neuroscience, Soochow University

John Marshall, Professor of Medical Science, Brown University. His early publications focused on the function of ionotropic glutamate receptors, kainate receptors. His group found the MAGUK (membrane-associated guanylate kinase) family of postsynaptic density (PSD) proteins can mediate kainate receptor clustering and anchoring at the membrane surface by binding the intracellular C-terminal tails of the receptors. Using NMR and fluorescence spectroscopy his group characterized the interaction between the ionotropic glutamate receptor subunit, GluR6, and the PDZ1 domain of the synaptic associated protein, PSD-95/SAP90. In addition to the contributions described above, his lab has focused on growth factor modulation of CaV1.2 and CaV1.3 neuronal L-type calcium channels. They demonstrated that the CaV1.3-induced regulation of pCREB arose through Shank interactions with CaV1.3, which, via Homer, linked the channels to IP3-sensitive calcium stores. In recent studies his lab has focused on Angelman syndrome (AS) BDNF signaling and developed a novel compound (CN2097) that is anticipated to lead to a new treatment for this disorder. In an innovative approach to develop high affinity PSD-95 PDZ modulators, they synthesized a selective cyclic peptide inhibitor, CN2097, targeting the PDZ-domain of PSD-95 that disrupts the interaction between Arc and PSD-95 to restore BDNF signaling and improve the induction of LTP in a mouse model of AS.

Representative publications:

1.Cao C, Rioult-Pedotti MS, Migani P, Yu CJ, Tiwari R, Parang K, Spaller MR, Goebel DJ, Marshall J. Impairment of TrkB-PSD-95 signaling in Angelman syndrome. PLoS Biol. 2013;11(2):e1001478.

2.Wu CH, Cao C, Kim JH, Hsu CH, Wanebo HJ, Bowen WD, Xu J, Marshall J. Trojan-horse nanotube on-command intracellular drug delivery. Nano Lett. 2012 Nov14;12(11):5475-80.

3.Gao L, Blair LA, Salinas GD, Needleman LA, Marshall J. Insulin-like growth factor-1 modulation of CaV1.3 calcium channels depends on Ca2+ release from IP3-sensitive stores and calcium/calmodulin kinase II phosphorylation of the alpha1 subunit EF hand. J Neurosci. 2006 Jun 7;26(23):6259-68.

4.Marshall J, Dolan BM, Garcia EP, Sathe S, Tang X, Mao Z, Blair LA. Calcium channel and NMDA receptor activities differentially regulate nuclear C/EBPbeta levels to control neuronal survival. Neuron. 2003 Aug 14;39(4):625-39.

5.Blair LA, Marshall J. IGF-1 modulates N and L calcium channels in a PI3-kinase-dependent manner. Neuron. 1997 Aug;19(2):421-9.

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