title: Corticotropin-releasing factor and urocortin regulate spine and synapse formation: structural basis for stress-induced neuronal remodeling and pathology.
abstract: Dendritic spines are important sites of excitatory neurotransmission in the brain with their function determined by their structure and molecular content. Alterations in spine number, morphology and receptor content are a hallmark of many psychiatric disorders, most notably those because of stress. We investigated the role of corticotropin-releasing factor (CRF) stress peptides on the plasticity of spines in the cerebellum, a structure implicated in a host of mental illnesses, particularly of a developmental origin. We used organotypic slice cultures of the cerebellum and restraint stress in behaving animals to determine whether CRF in vitro and stress in vivo affects Purkinje cell (PC) spine density. Application of CRF and urocortin (UCN) to cerebellar slice cultures increased the density of spines on PC signaling via CRF receptors (CRF-Rs) 1 and 2 and RhoA downregulation, although the structural phenotypes of the induced spines varied, suggesting that CRF-Rs differentially induce the outgrowth of functionally distinct populations of spines. Furthermore, CRF and UCN exert a trophic effect on the surface contact between synaptic elements by increasing active zones and postsynaptic densities and facilitating the alignment of pre- and post-synaptic membranes of synapses on PCs. In addition, 1 h of restraint stress significantly increased PC spine density compared with those animals that were only handled. This study provides unprecedented resolution of CRF pathways that regulate the structural machinery essential for synaptic transmission and provides a basis for understanding stress-induced mental illnesses.
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: N V
authors.initials: NV
authors.lastname: Gounko
authors.forename: J D
authors.initials: JD
authors.lastname: Swinny
authors.forename: D
authors.initials: D
authors.lastname: Kalicharan
authors.forename: S
authors.initials: S
authors.lastname: Jafari
authors.forename: N
authors.initials: N
authors.lastname: Corteen
authors.forename: M
authors.initials: M
authors.lastname: Seifi
authors.forename: R
authors.initials: R
authors.lastname: Bakels
authors.forename: J J L
authors.initials: JJ
authors.lastname: van der Want
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000166:cytology; D002614:Chelating Agents / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D036361:Peptide Hormones / Q000378:metabolism / Q000494:pharmacology*; D057907:Post-Synaptic Density / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011689:Purkinje Cells / Q000166:cytology* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology*; D013569:Synapses / Q000187:drug effects* / Q000648:ultrastructure; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C471210:2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine; D000814:Aniline Compounds; D002614:Chelating Agents; D005456:Fluorescent Dyes; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D036361:Peptide Hormones; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D050598:Vesicular Glutamate Transport Protein 1; C116607:antisauvagine 30; C570602:urotensin II-related peptide, 2-amino-3-(1,1'-bipheny-4-yl)propanoic acid(4)-; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D013779:Tetrodotoxin; D004533:Egtazic Acid; D003346:Corticotropin-Releasing Hormone; D020742:rhoA GTP-Binding Protein