title: Differential Tiam1/Rac1 activation in hippocampal and cortical neurons mediates differential spine shrinkage in response to oxygen/glucose deprivation.
abstract: Distinct neuronal populations show differential sensitivity to global ischemia, with hippocampal CA1 neurons showing greater vulnerability compared to cortical neurons. The mechanisms that underlie differential vulnerability are unclear, and we hypothesize that intrinsic differences in neuronal cell biology are involved. Dendritic spine morphology changes in response to ischemic insults in vivo, but cell type-specific differences and the molecular mechanisms leading to such morphologic changes are unexplored. To directly compare changes in spine size in response to oxygen/glucose deprivation (OGD) in cortical and hippocampal neurons, we used separate and equivalent cultures of each cell type. We show that cortical neurons exhibit significantly greater spine shrinkage compared to hippocampal neurons. Rac1 is a Rho-family GTPase that regulates the actin cytoskeleton and is involved in spine dynamics. We show that Rac1 and the Rac guanine nucleotide exchange factor (GEF) Tiam1 are differentially activated by OGD in hippocampal and cortical neurons. Hippocampal neurons express more Tiam1 than cortical neurons, and reducing Tiam1 expression in hippocampal neurons by shRNA enhances OGD-induced spine shrinkage. Tiam1 knockdown also reduces hippocampal neuronal vulnerability to OGD. This work defines fundamental differences in signalling pathways that regulate spine morphology in distinct neuronal populations that may have a role in the differential vulnerability to ischemia.
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Blanco-Suárez
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Fiuza
authors.affiliation: School of Clinical Sciences, St Michael's Hospital, University of Bristol, Bristol, UK.
authors.forename: Xun
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Clinical Sciences, St Michael's Hospital, University of Bristol, Bristol, UK.
authors.forename: Elavazhagan
authors.initials: E
authors.lastname: Chakkarapani
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Hanley
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010100:Oxygen / Q000378:metabolism; D011247:Pregnancy; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D010100:Oxygen; D002118:Calcium