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The mTOR pathway genes mTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function.
Nguyen, Lena H; Xu, Youfen; Nair, Maanasi; Bordey, Angelique.
Afiliación
  • Nguyen LH; Department Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA.
  • Xu Y; Departments of Neurosurgery and Cellular & Molecular Physiology, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Nair M; Departments of Neurosurgery and Cellular & Molecular Physiology, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Bordey A; Departments of Neurosurgery and Cellular & Molecular Physiology, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
bioRxiv ; 2024 Jan 06.
Article en En | MEDLINE | ID: mdl-37609221
Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activators, Rheb or mTOR, or biallelic inactivation of the mTORC1 repressors, Depdc5, Tsc1, or Pten in mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos