Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner.
Actin is the major cytoskeletal source of dendritic spines, which are highly specialized protuberances on the neuronal surface where excitatory synaptic transmission occurs (Harris, K.M., and S.B. Kater. 1994. Annu. Rev. Neurosci. 17:341-371; Yuste, R., and D.W. Tank. 1996. Neuron. 16:701-716). Stimulation of excitatory synapses induces changes in spine shape via localized rearrangements of the actin cytoskeleton (Matus, A. 2000. Science. 290:754-758; Nagerl, U.V., N. Eberhorn, S.B. Cambridge, and T. Bonhoeffer. 2004. Neuron. 44:759-767). However, what remains elusive are the precise molecular mechanisms by which different neurotransmitter receptors forward information to the underlying actin cytoskeleton. We show that in cultured hippocampal neurons as well as in whole brain synaptosomal fractions, RhoA associates with glutamate receptors (GluRs) at the spine plasma membrane. Activation of ionotropic GluRs leads to the detachment of RhoA from these receptors and its recruitment to metabotropic GluRs. Concomitantly, this triggers a local reduction of RhoA activity, which, in turn, inactivates downstream kinase RhoA-specific kinase, resulting in restricted actin instability and dendritic spine collapse. These data provide a direct mechanistic link between neurotransmitter receptor activity and the changes in spine shape that are thought to play a crucial role in synaptic strength.
Schubert
Vanessa
V
Cavalieri Ottolenghi Scientific Institute, Universita Degli Studi di Torino, Azienda Ospedaliera San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.
Da Silva
Jorge Santos
JS
Dotti
Carlos G
CG
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000196:embryology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D008565:Membrane Proteins / Q000032:analysis; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051304:Profilins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013347:Subcellular Fractions / Q000737:chemistry; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000199:Actins; D000577:Amides; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011189:Potassium Chloride; D051304:Profilins; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C501449:Dlg4 protein, rat; C104077:metabotropic glutamate receptor type 1; C108830:Y 27632