title: Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development.
abstract: GluA2-containing AMPA receptors (AMPARs) play a critical role in various aspects of neurodevelopment. However, the molecular mechanisms underlying these processes are largely unknown. We report here that the interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is necessary for neuron and cortical development. Using an interfering peptide (GluA2-G-Gpep) that specifically disrupts this interaction, we found that primary neuron cultures with peptide treatment displayed growth cone development deficits, impairment of axon formation, less dendritic arborization and lower spine protrusion density. Consistently, in vivo data with mouse brains from pregnant dams injected with GluA2-G-Gpep daily during embryonic day 8 to 19 revealed a reduction of cortical tract axon integrity and neuronal density in post-natal day 1 offspring. Disruption of GluA2-GAPDH interaction also impairs the GluA2-Plexin A4 interaction and reduces p53 acetylation in mice, both of which are possible mechanisms leading to the observed neurodevelopmental abnormalities. Furthermore, electrophysiological experiments indicate altered long-term potentiation (LTP) in hippocampal slices of offspring mice. Our results provide novel evidence that AMPARs, specifically the GluA2 subunit via its interaction with GAPDH, play a critical role in cortical neurodevelopment.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 Canada.
authors.forename: Frankie Hang Fung
authors.initials: FH
authors.lastname: Lee
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Su
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 Canada.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Xie
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 Canada.
authors.forename: Kyle Ethan
authors.initials: KE
authors.lastname: Wang
authors.affiliation: Department of Physiology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8 Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000196:embryology; D015220:Calcium Channels / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; C492110:Plxna4 protein, mouse; D018091:Receptors, AMPA; D011956:Receptors, Cell Surface; C068142:glyceraldehyde 3-phosphate dehydrogenase (304-313); D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D008239:Lysine; C104722:glutamate receptor ionotropic, AMPA 2