Unraveling psychiatric sub-phenotypes: The price of the reduction of myelin basic protein

by Giulia Poggi
Doctoral thesis
Date of Examination:2016-01-08
Date of issue:2016-07-29
Advisor:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Klaus-armin Nave
Referee:Prof. Dr. Mikael Simons
Persistent Address: http://dx.doi.org/10.53846/goediss-5777

 

 

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Abstract

English

Myelin, the proteolipidic layer that wraps around the axon, is one of the evolutionary advantages for animals with complex behaviour and reasoning. Myelin ensures axonal support and synchronised electrical communication among different brain areas. During the last two decades several studies have consistently reported myelin abnormalities in schizophrenia. Myelin Basic Protein (MBP), one of the major myelin structural proteins, has become more and more appealing for the attempt of understanding the role of myelin abnormalities in neuropsychiatric diseases. Due to its essential role in the correct formation of the myelin sheath, we wondered whether a reduction in MBP could be detrimental for the brain connectivity and functionality, hence leading to the appearance of specific symptomatology reported in schizophrenia. We characterised a mouse line expressing only 50% of MBP, i.e. the heterozygous strain of shiverer mice (here referred as Mbp+/- mouse). Through the combination of several methods (behavioural testing, magnetic resonance imaging, spectroscopy histology, electron microscopy and biochemical analyses), we proved that, upon ageing,the prefrontal cortex and its underlying white matter are highly sensitive to the lack of one MBP allele. We found reduced pre-pulse inhibition as a translationally valid behavioural readout of mental disease-associated network dysfunction, i.e. sensorimotor gating deficiency. As mechanisms likely contributing to this behavioural abnormality, we detected mild alteration in myelin ultrastructure and brain metabolism in association with microgliosis. Even though it is still unclear how and when the lowered MBP levels in schizophrenia are induced, we show for the first time that MBP reduction by itself does have mental disease relevant consequences
Keywords: Myelin Basic Protein (MBP); Schizophrenia; MRI; Electron microscopy; Prepulse Inhibition
 
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