Mechanistic target of rapamycin complex 1 (mTORC1) is an integration hub for extracellular and intracellular signals necessary for brain development. Hyperactive mTORC1 is found in autism spectrum disorder (ASD) characterized by atypical reactivity to sensory stimuli, among other symptoms. In Tuberous sclerosis complex (TSC) inactivating mutations in the or genes result in hyperactivation of the mTORC1 pathway and ASD. Here, we show that lack of light preference of the TSC zebrafish model, is caused by aberrant processing of light stimuli in the left dorsal habenula and fish have impaired function of the left dorsal habenula, in which neurons exhibited higher activity and lacked habituation to the light stimuli. These characteristics were rescued by rapamycin. We thus discovered that hyperactive mTorC1 caused aberrant habenula function resulting in lack of light preference. Our results suggest that mTORC1 hyperactivity contributes to atypical reactivity to sensory stimuli in ASD.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11214417 | PMC |
| http://dx.doi.org/10.1016/j.isci.2024.110149 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
SHP2 inhibition and adjuvant therapy synergistically target KIT-mutant GISTs via ERK1/2-regulated GSK3β/cyclin D1 pathway.
Clin Transl Med
February 2025
Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
Background: Most gastrointestinal stromal tumours (GISTs) are driven by KIT proto-oncogene, receptor tyrosine kinase (KIT). Targeted treatment with imatinib has been successful in primary GIST patients. However, resistance and relapse gradually develop due to secondary KIT mutations.
View Article and Find Full Text PDFComment on Chanoine et al. Is Hyperactive mTORC1 Signaling Responsible for the Phenotypic Expression (Diabetes, Hypoacusis) of the m.3243A>G Variant?
Diabetes
March 2025
Neurology Department, Neurology & Neurophysiology Center, Vienna, Austria.
Phenotypic rescue via mTOR inhibition in neuron-specific Pten knockout mice reveals AKT and mTORC1-site specific changes.
Mol Psychiatry
February 2025
Department of Neurology, FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, USA.
Phosphatase and Tensin Homolog (PTEN) is a dual-specific protein and lipid phosphatase that regulates AKT and downstream signaling of the mechanistic target of rapamycin (mTOR). PTEN functions as a tumor suppressor gene whose mutations result in PTEN Hamartoma Tumor Syndrome (PHTS) characterized by increased cancer risk and neurodevelopmental comorbidity. Here, we generated a novel neuron-specific Pten knock-out mouse model (Syn-Cre/Pten HOM) to test the ability of pharmacologic mTOR inhibition to rescue Pten mutation-associated disease phenotypes in vivo and in vitro.
View Article and Find Full Text PDFNeuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors.
Neurobiol Dis
February 2025
The University of Texas Southwestern Medical Center, Department of Neurology, Dallas, TX, United States of America; The University of Texas Southwestern Medical Center, Department of Psychiatry, Dallas, TX, United States of America; The University of Texas Southwestern Medical Center, Department of Pediatrics, Dallas, TX, United States of America; The University of Texas Southwestern Medical Center, Department of Neuroscience; O'Donnell Brain Institute, Dallas, TX, United States of America. Electronic address:
Loss of function in the subunits of the GTPase-activating protein (GAP) activity toward Rags-1 (GATOR1) complex, an amino-acid sensitive negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), is implicated in both genetic familial epilepsies and Neurodevelopmental Disorders (NDDs) (Baldassari et al., 2018). Previous studies have found seizure phenotypes and increased activity resulting from conditional deletion of GATOR1 function from forebrain excitatory neurons (Yuskaitis et al.
View Article and Find Full Text PDFSTAT1 Promotes PD-L1 Activation and Tumor Growth in Lymphangioleiomyomatosis.
bioRxiv
December 2024
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati; Cincinnati, OH 45267, USA.
Lymphangioleiomyomatosis (LAM) is a cystic lung disease that primarily affects women. LAM is caused by the invasion of metastatic smooth muscle-like cells into the lung parenchyma, leading to abnormal cell proliferation, lung remodeling and progressive respiratory failure. LAM cells have TSC gene mutations, which occur sporadically or in people with Tuberous Sclerosis Complex.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!