White matter integrity of the frontal brain and its relevance for catatonia and executive function
von Sahab Arinrad
Datum der mündl. Prüfung:2020-11-23
Erschienen:2021-11-22
Betreuer:Prof. Dr. Dr. Hannelore Ehrenreich
Gutachter:Prof. Dr. Dr. Hannelore Ehrenreich
Gutachter:Prof. Dr. Susann Boretius
Gutachter:Prof. Dr. Walter Paulus
Gutachter:Dr. Hauke Werner
Gutachter:Prof. Dr. Klaus-Armin Nave
Gutachter:Prof. Dr. Tiago Fleming Outeiro
Gutachter:Prof. Dr. Ralf Heinrich
Dateien
Name:Dissertation_Sahab_Arinrad_Clinical_Neurosci...pdf
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Description:Dissertation by Sahab Arinrad
Zusammenfassung
Englisch
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.
Keywords: white matter integrity; executive function; myelin; neuroinflammation; catatonia