Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior
Open accessAbstract
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.
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Disorganization of synaptic connectivity in the temporal lobe may compromise function of a network of brain regions underlying global brain dysfunction and ASD-like social deficits.
“the disorganization of synaptic connectivity in the temporal lobe, a central node in the social brain network (Gotts et al., 2012), may compromise function of a network of anatomically distinct brain regions that underlie global brain dysfunction and ASD-like social deficits (Normand et al., 2013; Tsai et al., 2012).”
From Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits (2014) · cites this paper as Normand et al., 2013
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- Authors
- Normand, E. A., Crandall, S. R., Thorn, C. A., Murphy, E. M., Voelcker, B., Browning, C., Machan, J. T., Moore, C. I., Connors, B. W., & Zervas, M.
- Affiliations
- Brown University (US)
- Corresponding author
- Zervas, Mark
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 78
- Issue
- 5
- Pages
- 895-909
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4529124
- OpenAlex
- W2044945188
- Cited by
- 67
- References
- 52
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 5 · 2016: 7 · 2015: 5 · 2014: 9
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- U.S. Department of Defense
- National Institutes of Health (5p50mh086400-05, MH086400)
- Brown Institute for Brain Science
- National Institute of Mental Health (P-50-MH-086400, P50 MH086400-03, MH086400)
- National Institute of Neurological Disorders and Stroke (7-R01NS045130-08, R01NS045130, R01NS050434, T32NS062443, NS062443-02)
- Division of Emerging Frontiers in Research and Innovation
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- tuberous sclerosis complex, TSC1, thalamus, thalamocortical circuits, developmental timing, seizures, compulsive grooming, neuronal physiology, autism spectrum disorder, intellectual disability, epilepsy, mouse brain development
- MeSH terms
- Tripartite Motif Proteins, Tuberous Sclerosis Complex 1 Protein, Animals, Animals, Newborn, Behavior, Animal, Biophysics, Brain Mapping, Cerebral Cortex, Electron Transport Complex IV, DNA-Binding Proteins, Electric Stimulation, Embryo, Mammalian, Myelin Basic Protein, Female, Glial Fibrillary Acidic Protein, Grooming, Hyperalgesia, Male, Membrane Potentials, Mice, Transgenic, Neural Pathways, Neurons, Nuclear Proteins, Pain Measurement, Phosphopyruvate Hydratase, Physical Stimulation, Pregnancy, Proteins, Seizures, Tamoxifen, Thalamus, Vibrissae, Linear Models, Sequence Deletion, Homeodomain Proteins, Patch-Clamp Techniques, Gene Expression Regulation, Developmental, Hand Strength, RNA, Untranslated, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Green Fluorescent Proteins, Mice, In Vitro Techniques
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