Abstract
Tuberous sclerosis is a developmental genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectual disability. The cause of these neurological deficits remains unresolved. Imaging studies suggest that the thalamus may be affected in tuberous sclerosis patients, but this has not been experimentally interrogated. We hypothesized that thalamic deletion of Tsc1 at distinct stages of mouse brain development would produce differential phenotypes. We show that mosaic Tsc1 deletion within thalamic precursors at embryonic day (E) 12.5 disrupts thalamic circuitry and alters neuronal physiology. Tsc1 deletion at this early stage is unique in causing both seizures and compulsive grooming in adult mice. In contrast, only a subset of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage. Our findings demonstrate that abnormalities in a discrete population of neurons can cause global brain dysfunction and that phenotype severity depends on developmental timing and degree of genetic mosaicism.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Video-Audio Media
MeSH terms
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Animals
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Animals, Newborn
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Behavior, Animal / physiology*
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Biophysics
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Brain Mapping
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Cerebral Cortex / physiology*
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DNA-Binding Proteins / metabolism
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Electric Stimulation
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Electron Transport Complex IV / metabolism
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Embryo, Mammalian
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Female
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Gene Expression Regulation, Developmental / genetics
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Glial Fibrillary Acidic Protein / metabolism
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Grooming / physiology
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Hand Strength / physiology
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Homeodomain Proteins / genetics
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Hyperalgesia / genetics
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In Vitro Techniques
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Linear Models
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Male
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Membrane Potentials / genetics
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Mice
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Mice, Transgenic
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Myelin Basic Protein / metabolism
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Neural Pathways / growth & development
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Neural Pathways / physiology
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Neurons / physiology*
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Nuclear Proteins / metabolism
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Pain Measurement
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Patch-Clamp Techniques
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Phosphopyruvate Hydratase / metabolism
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Physical Stimulation
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Pregnancy
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Proteins / genetics
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RNA, Untranslated
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Seizures / genetics
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Seizures / physiopathology
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Sequence Deletion / genetics*
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Tamoxifen / pharmacology
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Thalamus* / cytology
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Thalamus* / growth & development
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Thalamus* / physiology
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Tuberous Sclerosis Complex 1 Protein
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Tumor Suppressor Proteins / genetics*
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Ubiquitin-Protein Ligases
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Vibrissae / innervation
Substances
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DNA-Binding Proteins
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Gbx2 protein, mouse
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Glial Fibrillary Acidic Protein
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Gt(ROSA)26Sor non-coding RNA, mouse
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Homeodomain Proteins
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Myelin Basic Protein
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Nuclear Proteins
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Proteins
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RNA, Untranslated
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Tsc1 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tumor Suppressor Proteins
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Tamoxifen
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Green Fluorescent Proteins
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Electron Transport Complex IV
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Trim27 protein, mouse
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Ubiquitin-Protein Ligases
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Phosphopyruvate Hydratase