| dc.contributor.advisor | Schwab, Markus H. Dr. | |
| dc.contributor.author | Unterbarnscheidt, Tilmann | |
| dc.date.accessioned | 2015-12-01T10:30:37Z | |
| dc.date.available | 2015-12-01T10:30:37Z | |
| dc.date.issued | 2015-12-01 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0028-8650-8 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5394 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Conditional activation of NRG1 signaling in the brain modulates cortical circuitry | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Nave, Klaus-Armin Prof. Dr. | |
| dc.date.examination | 2015-05-05 | |
| dc.description.abstracteng | Neuregulin (NRG) 1 contains an epidermal growth factor (EGF)-like signaling domain
and serves as a ligand for receptor tyrosine kinases of the ErbB family. ErbB4, the
main neuronal NRG1 receptor in the brain, is enriched in GABAergic interneurons.
NRG1/ErbB4 signaling regulates different aspects of nervous system development
and synaptic plasticity in the mature brain. Variants of the human NRG1 and ERBB4
genes are genetic risk factors for schizophrenia, and inhibitory network dysfunctions
have been implicated in schizophrenia. For NRG1 most of the at-risk haplotypes are
located in non-coding regions, implicating that expression of NRG1 isoforms might
be altered in SZ. In line with this, increased NRG1 expression and ErbB4
hyperphosphorylation was observed in postmortem brains of schizophrenia patients,
suggesting that NRG1/ErbB4 hyperstimulation represents a possible
pathomechanisms in schizophrenia. To test this hypothesis several NRG1 loss- and
gain-of-function mouse models were employed to examine effects of altered NRG1
signaling on nervous system development and adult brain functions.
Conditional ablation of NRG1 in the embryonic cortex (Emx-Cre*Nrg1f/f mice) had no
effect on cortical development, whereas pan-neuronal overexpression of the CRDNRG1
isoform in transgenic mice lead to ErbB4 hyperactivation, altered numbers of
cortical interneurons, changes in dendritic spine morphology, ventricular
enlargement, increased anxiety-like behavior, and impaired sensorimotor gating.
These data suggest that the human NRG1 risk haplotypes exert a gain-of-function
effect.
To study NRG1/ErbB4 hyperstimulation in a more selective in vivo model, a
‚conditional’ transgenic mouse line (Stop-Nrg1) was generated, which allows Cre
recombinase-mediated CRD-NRG1 overexpression. This mouse line was examined
in combination with different Cre ‚driver’ lines to model distinct temporal and spatial
aspects of CRD-NRG1 overexpression in the brain. Postnatal onset of CRD-NRG1
overexpression had only minor effects on nervous system development and
behavior, whereas early embryonic onset of NRG1 hyperstimulation lead to
hyperactivity, consistent with the neurodevelopmental hypothesis of schizophrenia.
Cortical-restricted CRD-NRG1 overexpression had no effect on ventricular size or
sensorimotor gating, indicating functions of CRD-NRG1 signaling in subcortical
networks. Finally, CRD-NRG1 was present in synaptosomal fractions and appears to
recruit LIMK1-cofilin signaling, providing a potential mechanism for the regulation of
dendritic spine dynamics. | de |
| dc.contributor.coReferee | Ehrenreich, Hannelore Prof. Dr. Dr. | |
| dc.subject.eng | NRG1 | de |
| dc.subject.eng | ErbB4 | de |
| dc.subject.eng | Neuregulin | de |
| dc.subject.eng | Conditional overexpression | de |
| dc.subject.eng | Schizophrenia | de |
| dc.subject.eng | SZ | de |
| dc.subject.eng | Nervous system development | de |
| dc.subject.eng | Behavior | de |
| dc.subject.eng | Ventricular enlargement | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0028-8650-8-3 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 841254745 | |