| dc.contributor.advisor | Ehrenreich, Hannelore Prof. Dr. Dr. | |
| dc.contributor.author | Arinrad, Sahab | |
| dc.date.accessioned | 2021-11-22T16:09:46Z | |
| dc.date.available | 2021-11-22T16:09:46Z | |
| dc.date.issued | 2021-11-22 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0008-5999-8 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8974 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | White matter integrity of the frontal brain and its relevance for catatonia and executive function | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Ehrenreich, Hannelore Prof. Dr. Dr. | |
| dc.date.examination | 2020-11-23 | |
| dc.description.abstracteng | Catatonia is a CNS derived psychomotor syndrome comprising disturbed volition and aberrant
motor and behavioral features. Targeted and effective treatment today is scarce and further
impeded by its heterogeneous clinical representation across various CNS disorders. Moreover,
respective research on the etiology and underlying cellular pathomechanisms are hampered by
sustained conceptual limitations, inadequate clinical rating scales and the lack of reliable animal
models.
To this end, we had previously reported a catatonia-like phenotype in C57Bl/6 mice
heterozygous for the major myelin genes Cnp and Mbp upon progressed age, along with
indications of low-grade neuroinflammation. In the first project of my thesis, I thus addressed
the question whether neuroinflammation of subcortical white matter is causative to catatonia in
both mice and man. Neurological assessment of schizophrenic subjects (n=1095) revealed a
high prevalence of catatonic signs (25%), which were more pronounced in carriers of a CNP
loss-of-sunction SNP (rs207106-AA). Additionally, elevated signs of white matter
hyperintensities were observed in carriers of the SNP in a general population sample by
neuroimaging. Cnp-null mutant mice exhibit catatonic signs as early as 8 weeks of age.
Importantly, microglia targeted treatment via the CSF1 receptor inhibitor PLX5622,
successfully prevented the occurrence of the phenotype upon early treatment and further
alleviated catatonic signs even at progressed age. The beneficial impact of PLX5622 on mouse
behavior was accompanied by sustained reduction of neuropathology, i.e. microgliosis and
neurodegeneration. Collectively these findings indeed suggest key involvement of impaired
white matter integriy and neuroinflammation in the etiology of catatonia.
Based on a follow-up study, which revealed a strong correlation of catatonia and executive
dysfunction in mice and man, the objective of the second project was to determine the relevance
of white matter integrity of the frontal brain in the etiology of the psychomotor syndrome. A
novel mouseline, lacking the major myelin gene Plp1 in Emx1 expressing ventricular zone stem
cells of the forebrain (cKO), was characterized on a behavioral and neuropathological scope.
Longitudinal and elaborate behavioral assessment revealed an isolated catatonia-executive
dysfunction in cKO mice of both genders, while no other behavioral domain was affected.
Neuropathology revealed significant astro- and microgliosis along with neurodegeneration,
exclusively in frontal strucutres such as the fimbria and corpus callosum, thereby confirming the
crucial importance of white matter integrity of the frontal brain in the observed catatonia-like
phenotype in the here reported mouse models. | de |
| dc.contributor.coReferee | Boretius, Susann Prof. Dr. | |
| dc.contributor.thirdReferee | Paulus, Walter Prof. Dr. | |
| dc.contributor.thirdReferee | Werner, Hauke Dr. | |
| dc.contributor.thirdReferee | Nave, Klaus-Armin Prof. Dr. | |
| dc.contributor.thirdReferee | Outeiro, Tiago Fleming Prof. Dr. | |
| dc.contributor.thirdReferee | Heinrich, Ralf Prof. Dr. | |
| dc.subject.eng | white matter integrity | de |
| dc.subject.eng | executive function | de |
| dc.subject.eng | myelin | de |
| dc.subject.eng | neuroinflammation | de |
| dc.subject.eng | catatonia | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0008-5999-8-5 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1778294162 | |