title: Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior.
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.
authors.affiliation: Department of Neuroscience, Division of Biology and Medicine, Brown University, 70 Ship Street, Providence, RI 02903, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Normand
authors.forename: Shane R
authors.initials: SR
authors.lastname: Crandall
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Thorn
authors.forename: Emily M
authors.initials: EM
authors.lastname: Murphy
authors.forename: Bettina
authors.initials: B
authors.lastname: Voelcker
authors.forename: Catherine
authors.initials: C
authors.lastname: Browning
authors.forename: Jason T
authors.initials: JT
authors.lastname: Machan
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Moore
authors.forename: Barry W
authors.initials: BW
authors.lastname: Connors
authors.forename: Mark
authors.initials: M
authors.lastname: Zervas
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology*; D001703:Biophysics; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004558:Electric Stimulation; D003576:Electron Transport Complex IV / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006120:Grooming / Q000502:physiology; D018737:Hand Strength / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics; D006930:Hyperalgesia / Q000235:genetics; D066298:In Vitro Techniques; D016014:Linear Models; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009434:Neural Pathways / Q000254:growth & development / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010812:Physical Stimulation; D011247:Pregnancy; D011506:Proteins / Q000235:genetics; D022661:RNA, Untranslated; D012640:Seizures / Q000235:genetics / Q000503:physiopathology; D017384:Sequence Deletion / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology; D013788:Thalamus / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D014738:Vibrissae / Q000294:innervation; D000070584:Tripartite Motif Proteins
chemical_list: D004268:DNA-Binding Proteins; D003576:Electron Transport Complex IV; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D004676:Myelin Basic Protein; D009687:Nuclear Proteins; D010751:Phosphopyruvate Hydratase; D011506:Proteins; D022661:RNA, Untranslated; D013629:Tamoxifen; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C513182:Gbx2 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C000624651:Tsc1 protein, mouse; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins