Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the presence of benign tumors, called hamartomas, which can affect virtually every organ system of the body. The hallmark of TSC and the predominant cause of morbidity in this disease are the neurological symptoms, such as epilepsy, autism and mental retardation, which occur in 95% of affected individuals. Over the last decade, significant progress has been made in identifying a function for TSC in regulating protein synthesis and cell size. However, the cause of the neurological symptoms in TSC patients has not yet been resolved. We propose a set of experiments to investigate neuronal connectivity and network formation in mouse models of TSC. These experiments are based on our recent observation that TSC pathway components are expressed in axons of hippocampal neurons at high levels starting with the initial stages of axonal polarization. Furthermore, we find that in mice lacking Tsc2, topographic mapping of connections in the brain are aberrant compared to wild-type mice. These findings have led us to hypothesize that TSC proteins are crucial not only for determining cell size, but also for determining axonal connectivity in the brain. We propose two sets of experiments to elucidate the role played by TSC1/TSC2 proteins in the establishment of axonal polarity and the mediation of axonal pathfinding. By using dissociated cultures, acute brain slices, and brain sections, we will first characterize the role of TSC proteins in the establishment of neuronal polarity. In the second phase of the project, we will characterize the role of TSC proteins in axon pathfinding and growth cone dynamics. Ultimately, our work will determine the role of TSC proteins in neuronal network formation by examining the visual pathways in Tsc-deficient mice - the best-studied and most accessible axon pathway in the central nervous system. The operations of TSC protein complex may be the key to a fuller understanding of the abnormal neural networks of TSC. Our results, thus, may suggest further avenues of exploration to illuminate the complex causes of the devastating neurological symptoms that characterize TSC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058956-04
Application #
7848074
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Morris, Jill A
Project Start
2007-06-15
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$365,991
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Lipton, Jonathan O; Boyle, Lara M; Yuan, Elizabeth D et al. (2017) Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy. Cell Rep 20:868-880
Lipton, Jonathan O; Yuan, Elizabeth D; Boyle, Lara M et al. (2015) The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation. Cell 161:1138-1151
Zhang, Jiangwei; Kim, Jinhee; Alexander, Angela et al. (2013) A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat Cell Biol 15:1186-96
Tsai, Peter T; Hull, Court; Chu, YunXiang et al. (2012) Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488:647-51
Sahin, Mustafa (2012) Targeted treatment trials for tuberous sclerosis and autism: no longer a dream. Curr Opin Neurobiol 22:895-901
Nie, Duyu; Sahin, Mustafa (2012) A genetic model to dissect the role of Tsc-mTORC1 in neuronal cultures. Methods Mol Biol 821:393-405
Tsai, Peter; Sahin, Mustafa (2011) Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex. Curr Opin Neurol 24:106-13
Khwaja, Omar S; Sahin, Mustafa (2011) Translational research: Rett syndrome and tuberous sclerosis complex. Curr Opin Pediatr 23:633-9
Kye, Min Jeong; Neveu, Pierre; Lee, Yong-Seok et al. (2011) NMDA mediated contextual conditioning changes miRNA expression. PLoS One 6:e24682
Sahin, Mustafa; Miller, Ian; Holmes, Gregory L et al. (2011) Pediatric epileptology. Epilepsy Behav 22:32-7

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