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«Inauguraldissertation zur Erlangen der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der ...»

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The role of raptor during brain development

and in adult forebrain neurons

Inauguraldissertation

zur

Erlangen der Würde eines Doktors der Philosophie

vorgelegt der

Philosophisch-Naturwissenschaftlichen Fakultät

der Universität Basel

von

Regula Maria Lustenberger

aus Romoos (LU)

Biozentrum der Universität Basel

Basel, August 2012

Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von

Prof. Dr. Markus A. Rüegg

Prof. Dr. Kaspar E. Vogt

Basel, den 26. Juni 2012 Prof. Dr. Martin Spiess Dekan der Philosophisch-Naturwissenschaftlichen Fakultät Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz“ lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licences/by-nc-nd/2.5/ch eingesehen werden.

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Quelle: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/ Datum: 3.4.2009 “Nerve paths are something fixed, ended, immutable. Everything may die; nothing may be regenerated.” Santiago Ramón y Cajal This citation from the founder of the “neuron theory” and probably one of the most important and popular scientist ever since in the field of neuroscience is escorting me since my Master studies. At that time, I worked on neuronal progenitor cells and their capacity to proliferate after spinal cord injury. As it is well described today, the mammalian nervous system is not a completely post-mitotic tissue but rather harbors certain pools of cells that are able to divide and to functionally integrate into pre-existing networks. Thus, the conclusion I draw after my Master studies was the following: as brilliant Mr. Cajal was, at least in his statement about the regenerative capacity of the nervous system he eventually was wrong.

Now, after several additional years in neuroscience, working on a PhD project focusing on synaptic plasticity in the adult mouse brain, there is another statement of Santiago Ramón y Cajal that I have to reconsider: e.g. with focus on individual synapses or spines, the attributes “fixed, ended, immutable” do not fit any more into the current understanding of synaptic rearrangement, spine motility or very generally spoken to the theory of synaptic plasticity and learning and memory.

With these notions, by no means I intend to subtract the remarkable and valuable contribution of Santiago Ramón y Cajal to modern neuroscience. Rather, they shall serve as an illustration of how convertible knowledge is. The driving force of science to constantly gain new insights into any kind of mechanism is ultimately followed by the consequence that pre-existing knowledge is dropped or modified. Due to this fact, as a scientist one constantly proceeds on a tightrope walk, trading well accepted knowledge off against the basic principle of science – that is constant questioning and discovering. Therefore, what the citation of Santiago Ramón y Cajal – or in other words studying the nervous system during my Master’s and PhD – taught me is that in general nothing may be fixed or ended or immutable… Table of content Regula M. Lustenberger

TABLE OF CONTENT

1 SUMMARY

2 LIST OF ABBREVIATIONS

3 INTRODUCTION

3.1 The mTORC1 pathway

3.1.1 Domain structure of mTOR and assembly of mTORC1 and mTORC2

3.1.2 Upstream control of mTORC1





3.1.3 Downstream targets of mTORC1

3.1.4 Feedback inhibition within mTORC1 signaling

3.2 mTORC1 in the developmental and adult brain

3.2.1 mTORC1 in neuronal development

3.2.2 mTORC1 in brain physiology and pathologies

3.3 mTORC1 in synaptic plasticity and learning and memory

3.3.1 Mechanisms of synaptic plasticity

3.3.2 The role of mTORC1 in synaptic plasticity

3.4 The aim of the study

4 RESULTS

4.1 Paper 1 (RcKO)

4.2 Paper 2 (RAbKO)

4.3 Additional findings

4.3.1 Results from αCamKII-CreERT2 mediated rptor knockout

4.3.2 Material and methods of αCamKII-CreERT2 experiments

5 CONCLUDING REMARKS

6 OUTLOOK

7 REFERENCES

ACKNOWLEDGMENT

–  –  –

1 SUMMARY mTOR is a serine/threonine protein kinase that appears in two functionally distinct multi-protein complexes. mTOR together with the scaffold protein raptor forms mTOR complex1 (mTORC1) that is inhibited in its function by rapamycin. In contrast, mTORC2 is dependent on the interaction with rictor and is considered to be rapamycin insensitive. mTORC1 controls a wide range of cellular processes, including protein synthesis, ribosome biogenesis, cell growth, gene transcription, autophagy and metabolism. In the developing CNS, mTORC1 was shown to be involved in axonal outgrowth and navigation, dendritic arborization as well as spine and filopodia formation. In the adult brain, the dysfunction of mTORC1 signaling has been linked to several neurodegenerative disorders like Parkinson’s, Alzheimer’s, or Huntington’s disease and to some mental disorders, such as schizophrenia or autism spectrum disorders. However, it is not known whether altered mTORC1 signaling is cause or consequence of those pathologies. In addition, mTORC1 has also been suggested to be involved in synaptic plasticity and the process of learning and memory. To study the role of mTORC1 during development as well as in the adult stage of the brain, we deleted the mTORC1-defining component raptor by crossing floxed rptor mice with mice expressing the Crerecombinase under the control of the Nestin promoter (RAbKO mice) or under the control of the αCamKII promoter (RcKO mice), respectively.

Analysis of the RAbKO mice revealed that several aspects of brain development are critically controlled by mTORC1. RAbKO mice showed a pronounced microcephaly which is evenly expressed in all brain structures and gets apparent at E17.5. The observed change in brain size is likely due to reduced cell size and cell number. The latter is potentially the result of two mechanisms that are altered in RAbKO mice. First, raptor-depletion results in an increased incidence of apoptosis at late embryonic stages. Secondly, RAbKO mice show reduced proliferation at E17.5 and prolonged cell cycle length earlier during development. Furthermore, RAbKO mice show deficits in glial differentiation, probably mediated by altered STAT3 signaling that is observed in those mice.

Moreover, ablation of mTORC1 activity during brain development affects cortical and hippocampal layering.

Due to the immediate postnatal lethality of RAbKO mice, there was need for the generation of a second knockout-mouse strain based on α-CamKII-Cre mediated recombination to further analyze the postnatal role of mTORC1 in the brain (RcKO mice). The data that were obtained from this mouse model indicate that mTORC1 is involved in cell size maintenance in adult neurons but does not affect apoptosis in the adult brain. Further, RcKO mice display a distinct deficit in learning and memory in the Morris water maze. Under long inter-training-interval conditions where consolidation takes place within Page | 6 Summary Regula M. Lustenberger a time window that relies on de novo protein synthesis, the learning and memory performance of RcKO mice is reduced. This deficit can be overcome by an acquisition phase with short inter-trainingintervals. Additionally, RcKO mice do exhibit impairments in fear extinction learning whereas the learning as well as context- and cue-memory is not affected in the fear conditioning paradigm in RcKO mice compared to control. These behavioral phenotypes are resembled by impaired E-LTP and L-LTP maintenance in RcKO mice. In addition to these plasticity-related aspects, also basal synaptic function of CA1 hippocampal neurons is altered in RcKO mice.

In summary, the data obtained from the two mouse models provide evidence that mTORC1 signaling controls several aspects of brain development and adult brain function. While during embryogenesis mainly cellular processes such as proliferation, differentiation and growth are affected by raptor deficiency, in the adult brain – besides the cell size control – primarily synaptic and plasticity-related functions depend on mTORC1 signaling. Further examination of mTORC1-related functions such as autophagy and mitochondrial regulation in RcKO mice potentially will provide new insights into mechanism of brain aging and neurodegenerative diseases, both of which are processes that are discussed to be dependent on mTORC1 signaling.

–  –  –

3 INTRODUCTION

The history of TOR (target of rapamycin) started in the 1960’s with a Canadian expedition to Easter Island (in the native language named Rapa Nui) that aimed to collect plant and soil samples for subsequent analysis. One of such a soil sample contained the bacterium Streptomyces hygroscopicus that was found to produce a secondary metabolite, rapamycin, which displayed potent antifungal activity (Sehgal et al., 1975). After this first characterization of rapamycin as an antifungal agent and the finding of additional qualities such as immunosuppressive and cytostatic, the molecular targets of rapamycin were discovered in a yeast genetic screen by the group of M.N. Hall in Basel in 1991.

These targets were named TOR1 and TOR2 (Heitman et al., 1991). Today, several years of investigation later, the field of knowledge about the target of rapamycin has grown exponentially. TOR is a large serine/threonine protein kinase that is conserved from yeast to human and is found in two distinct multi-protein complexes named TORC1 and TORC2 (Loewith et al., 2002).

In contrast to yeast, only one TOR ortholog has been identified in higher eukaryotes. The mammalian TOR (mTOR) forms two distinct protein complexes termed mTORC1 and mTORC2, respectively. mTORC1 and mTORC2 signaling are involved in a variety of cellular processes such as protein synthesis, autophagy, cell cycle progression, growth, metabolism, cytoskeletal organization and cell survival. As a consequence of this wide range of action, mTOR has been linked to cancer, metabolic disease such as obesity, fatty liver disease, insulin resistance and diabetes as well as several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, or Huntington’s disease and to some mental disorders, such as schizophrenia or autism spectrum disorders (Laplante and Sabatini, 2012). Proper basic neuronal function was recently intensively discussed to be dependent on balanced mTORC1 signaling. However, little is known about the mechanisms underlying altered mTORC1 signaling that was observed in a broad range of neuropathologies and brain disorders.

Given the fact that mTOR plays a central role in growing and dividing cells and additionally in post-mitotic adult tissues, it is still a challenge to therapeutically target and modulate this pathway specifically in respect to the above mentioned pathologies. Therefore, a better understanding of the mTOR signaling pathway in different organs and cell types in a healthy state as well as under disease conditions is crucial for future potential therapeutic targeting. The data presented here are the first that describe the genetically based depletion of mTORC1 signaling specifically in the developing brain and in adult excitatory neurons, respectively. In this study, we provide evidence for a crucial role of mTORC1 signaling during brain development and in adult forebrain neurons and describe the detrimental effects of the lack of mTORC1 activity during embryogenesis and the diminished synaptic efficiency accompanied by reduced cognitive abilities resulting from an inactivation of mTORC1 in the adult forebrain.

–  –  –



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