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Corticotropin-releasing factor and urocortin regulate spine and synapse formation: structural basis for stress-induced neuronal remodeling and pathology

Molecular Psychiatry volume 18, pages 86–92 (2013)Cite this article

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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.

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Acknowledgements

We thank Scott Rodaway and all members of the bio-resources team of the School of Pharmacy and Biomedical Sciences, University of Portsmouth, for assistance with experimental work.

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Author notes

  1. N V Gounko

    Present address: 4Current address: Scripps Research Institute, La Jolla, CA USA.,

  2. N V Gounko and J D Swinny: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    N V Gounko, D Kalicharan, S Jafari & J J L van der Want

  2. Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK

    J D Swinny, N Corteen & M Seifi

  3. Department of Medical Physiology, Graduate School of Behavioral and Cognitive Neurosciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    R Bakels

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Correspondence to J J L van der Want.

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Gounko, N., Swinny, J., Kalicharan, D. et al. Corticotropin-releasing factor and urocortin regulate spine and synapse formation: structural basis for stress-induced neuronal remodeling and pathology. Mol Psychiatry 18, 86–92 (2013). https://doi.org/10.1038/mp.2012.43

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