Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain
Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting the brain and other vital organs. Neurological symptoms include epilepsy, intellectual disability, and autism. TSC is caused by a loss-of-function mutation in the TSC1 or TSC2 gene. These gene products form a p...
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2018.00409/full |
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| author | Rebecca L. Cox Rebecca L. Cox Froylan Calderon de Anda Froylan Calderon de Anda Tomer Mangoubi Akira Yoshii Akira Yoshii |
| author_facet | Rebecca L. Cox Rebecca L. Cox Froylan Calderon de Anda Froylan Calderon de Anda Tomer Mangoubi Akira Yoshii Akira Yoshii |
| author_sort | Rebecca L. Cox |
| collection | DOAJ |
| description | Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting the brain and other vital organs. Neurological symptoms include epilepsy, intellectual disability, and autism. TSC is caused by a loss-of-function mutation in the TSC1 or TSC2 gene. These gene products form a protein complex and normally suppress mammalian target of rapamycin (mTOR) activity. mTOR inhibitors have been used to treat subependymal glioma (SEGA) that is a brain tumor characteristic of TSC. However, neuropathology of TSC also involves dysregulated cortical circuit formation including neuronal migration, axodendritic differentiation, and synapse formation. It is currently unknown to what extent mTOR signaling inhibitors correct an alteration in neuronal morphology that have already formed prior to the treatment. Here, we address the efficacy of rapamycin treatment on neuronal migration and dendrite formation. Using in utero electroporation, we suppressed Tsc1 expression in a fraction of neuronal progenitor cells during the fetal period. In embryonic brain slices, we found that more Tsc1-suppressed cells remained within the periventricular zone, and rapamycin treatment facilitated neuronal migration. Postnatally, Tsc1-suppressed pyramidal neurons showed more complex branching of basal dendrites and a higher spine density at postnatal day (P) 28. Aberrant arborization was normalized by rapamycin administration every other day between P1 and P13 but not P15 and P27. In contrast, abnormal spine maturation improved by rapamycin treatment between P15 and P27 but not P1 and P13. Our results indicate that there are multiple critical windows for correcting different aspects of structural abnormalities in TSC, and the responses depend on the stage of neuronal circuit formation. These data warrant a search for an additional therapeutic target to treat neurological symptoms of TSC. |
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| language | English |
| last_indexed | 2024-12-22T03:53:22Z |
| publishDate | 2018-11-01 |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-a3553d549a3a4d84ae0c883a529bb43e2022-12-21T18:39:57ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-11-011110.3389/fnmol.2018.00409411371Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed BrainRebecca L. Cox0Rebecca L. Cox1Froylan Calderon de Anda2Froylan Calderon de Anda3Tomer Mangoubi4Akira Yoshii5Akira Yoshii6Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, United StatesFeil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United StatesDepartment of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, United StatesCenter for Molecular Neurobiology Hamburg, Research Group Neuronal Development, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, United StatesDepartment of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, United StatesDepartment of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL, United StatesTuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting the brain and other vital organs. Neurological symptoms include epilepsy, intellectual disability, and autism. TSC is caused by a loss-of-function mutation in the TSC1 or TSC2 gene. These gene products form a protein complex and normally suppress mammalian target of rapamycin (mTOR) activity. mTOR inhibitors have been used to treat subependymal glioma (SEGA) that is a brain tumor characteristic of TSC. However, neuropathology of TSC also involves dysregulated cortical circuit formation including neuronal migration, axodendritic differentiation, and synapse formation. It is currently unknown to what extent mTOR signaling inhibitors correct an alteration in neuronal morphology that have already formed prior to the treatment. Here, we address the efficacy of rapamycin treatment on neuronal migration and dendrite formation. Using in utero electroporation, we suppressed Tsc1 expression in a fraction of neuronal progenitor cells during the fetal period. In embryonic brain slices, we found that more Tsc1-suppressed cells remained within the periventricular zone, and rapamycin treatment facilitated neuronal migration. Postnatally, Tsc1-suppressed pyramidal neurons showed more complex branching of basal dendrites and a higher spine density at postnatal day (P) 28. Aberrant arborization was normalized by rapamycin administration every other day between P1 and P13 but not P15 and P27. In contrast, abnormal spine maturation improved by rapamycin treatment between P15 and P27 but not P1 and P13. Our results indicate that there are multiple critical windows for correcting different aspects of structural abnormalities in TSC, and the responses depend on the stage of neuronal circuit formation. These data warrant a search for an additional therapeutic target to treat neurological symptoms of TSC.https://www.frontiersin.org/article/10.3389/fnmol.2018.00409/fulltuberous sclerosis complexneuronal migrationsynapse formationcritical periodrapamycin |
| spellingShingle | Rebecca L. Cox Rebecca L. Cox Froylan Calderon de Anda Froylan Calderon de Anda Tomer Mangoubi Akira Yoshii Akira Yoshii Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain Frontiers in Molecular Neuroscience tuberous sclerosis complex neuronal migration synapse formation critical period rapamycin |
| title | Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain |
| title_full | Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain |
| title_fullStr | Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain |
| title_full_unstemmed | Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain |
| title_short | Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain |
| title_sort | multiple critical periods for rapamycin treatment to correct structural defects in tsc 1 suppressed brain |
| topic | tuberous sclerosis complex neuronal migration synapse formation critical period rapamycin |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2018.00409/full |
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