Header

UZH-Logo

Maintenance Infos

Knocking Out Nogo-A: Effects on Brain and Behavior


Willi, R. Knocking Out Nogo-A: Effects on Brain and Behavior. 2009, University of Zurich / ETH Zurich, Faculty of Medicine.

Abstract

The membrane protein Nogo-A is widely expressed within the central nervous system, and its expression can be found in oligodendrocyte myelin as well as neurons. Nogo-A expression in myelin directly correlates with its well known functional relevance in terms of restricting axonal regeneration and structural plasticity. Neuronal Nogo-A shows a highly developmentally-regulated and regionally-selective distribution pattern, which strongly points to additional functions for Nogo-A, particularly in neurodevelopmental processes and plasticity. However, specific roles for Nogo-A beyond myelin-derived inhibition still largely remain to be unraveled.
The present thesis starts with a review focusing on the general functioning of Nogo-A and on recent developments of therapeutic agents mediating enhanced regeneration and plasticity after injury to the central nervous system (Chapter 1). Next, a critical review of findings originating from human genetics and experimental studies and implying Nogo-A and Nogo receptor (NgR) in neuropsychiatric disorders such as schizophrenia follows (Chapter 2).
The research described in the following chapters aimed at evaluating the impact of Nogo-A deletion on brain and behavior in order to characterize novel roles that Nogo-A may play in the intact nervous system. For this purpose, a mouse model of constitutive genetic Nogo-A deficiency was employed to explore the effect of Nogo-A absence (i) on basic behavioral processes that rely on the integrity of brain areas with high neuronal Nogo-A expression and (ii) on brain and behavioral traits that are of specific importance to schizophrenia, as predisposition in schizophrenia has been linked to Nogo-A.
The first series of experiments (Chapter 3) revealed that adult mice lacking Nogo-A are unaffected across a variety of behavioral domains, including several basic as well as particular anxiety- and learning-related behavioral functions. However, these mice displayed increased motor coordination and balance abilities. In addition, they showed spontaneous hyperactivity in a circadian-dependent manner and hyperactivity after systemic challenge with the indirect dopaminergic agonist amphetamine. This study thus demonstrates that global absence of Nogo-A can lead to the emergence of specific behavioral changes in adulthood and in turn suggests novel roles for Nogo-A in the modulation of specific motor and dopaminergic functions.
Detailed examination of functional and structural brain properties with a special emphasis on tests relevant for schizophrenia-related pathology in the next series of experiments (Chapter 4) demonstrated that life-long absence of Nogo-A is associated with multiple behavioral, pharmacological, and neurochemical abnormalities: Mice lacking Nogo-A displayed several behavioral phenotypes resembling manifestations in schizophrenic patients, which were accompanied by increased growth marker expression and dysregulations in monoaminergic systems in specific striatal and limbic structures. Importantly, no such phenotype was detected in adult wild-type mice after acute suppression of Nogo-A using antibodies. These findings thus suggest that Nogo-A may constitute a critical factor in mechanisms underlying brain disorders of developmental origin such as schizophrenia, which would be consistent with the idea that Nogo-A plays a key role in brain wiring during development.
Together, the experimental investigations presented in this thesis represent the first thorough analysis of the consequences of constitutive absence of Nogo-A on brain and behavior and provide significant insights into the functional relevance of Nogo-A in normal as well as pathological brain function.

Abstract

The membrane protein Nogo-A is widely expressed within the central nervous system, and its expression can be found in oligodendrocyte myelin as well as neurons. Nogo-A expression in myelin directly correlates with its well known functional relevance in terms of restricting axonal regeneration and structural plasticity. Neuronal Nogo-A shows a highly developmentally-regulated and regionally-selective distribution pattern, which strongly points to additional functions for Nogo-A, particularly in neurodevelopmental processes and plasticity. However, specific roles for Nogo-A beyond myelin-derived inhibition still largely remain to be unraveled.
The present thesis starts with a review focusing on the general functioning of Nogo-A and on recent developments of therapeutic agents mediating enhanced regeneration and plasticity after injury to the central nervous system (Chapter 1). Next, a critical review of findings originating from human genetics and experimental studies and implying Nogo-A and Nogo receptor (NgR) in neuropsychiatric disorders such as schizophrenia follows (Chapter 2).
The research described in the following chapters aimed at evaluating the impact of Nogo-A deletion on brain and behavior in order to characterize novel roles that Nogo-A may play in the intact nervous system. For this purpose, a mouse model of constitutive genetic Nogo-A deficiency was employed to explore the effect of Nogo-A absence (i) on basic behavioral processes that rely on the integrity of brain areas with high neuronal Nogo-A expression and (ii) on brain and behavioral traits that are of specific importance to schizophrenia, as predisposition in schizophrenia has been linked to Nogo-A.
The first series of experiments (Chapter 3) revealed that adult mice lacking Nogo-A are unaffected across a variety of behavioral domains, including several basic as well as particular anxiety- and learning-related behavioral functions. However, these mice displayed increased motor coordination and balance abilities. In addition, they showed spontaneous hyperactivity in a circadian-dependent manner and hyperactivity after systemic challenge with the indirect dopaminergic agonist amphetamine. This study thus demonstrates that global absence of Nogo-A can lead to the emergence of specific behavioral changes in adulthood and in turn suggests novel roles for Nogo-A in the modulation of specific motor and dopaminergic functions.
Detailed examination of functional and structural brain properties with a special emphasis on tests relevant for schizophrenia-related pathology in the next series of experiments (Chapter 4) demonstrated that life-long absence of Nogo-A is associated with multiple behavioral, pharmacological, and neurochemical abnormalities: Mice lacking Nogo-A displayed several behavioral phenotypes resembling manifestations in schizophrenic patients, which were accompanied by increased growth marker expression and dysregulations in monoaminergic systems in specific striatal and limbic structures. Importantly, no such phenotype was detected in adult wild-type mice after acute suppression of Nogo-A using antibodies. These findings thus suggest that Nogo-A may constitute a critical factor in mechanisms underlying brain disorders of developmental origin such as schizophrenia, which would be consistent with the idea that Nogo-A plays a key role in brain wiring during development.
Together, the experimental investigations presented in this thesis represent the first thorough analysis of the consequences of constitutive absence of Nogo-A on brain and behavior and provide significant insights into the functional relevance of Nogo-A in normal as well as pathological brain function.

Statistics

Altmetrics

Additional indexing

Item Type:Dissertation
Referees:Schwab M E
Communities & Collections:04 Faculty of Medicine > Brain Research Institute
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Date:2009
Deposited On:23 Feb 2010 08:35
Last Modified:05 Apr 2016 14:00
Number of Pages:129
Publisher DOI:https://doi.org/10.3929/ethz-a-005930938
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&con_lng=GER&func=find-b&find_code=SYS&request=005930938

Download

Full text not available from this repository.
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations