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<p>Maternal inflammatory response (MIR) during early mouse gestation induces a cascade of physiological and behavioral changes associated with autism spectrum disorder (ASD). We have shown that mild MIR causes chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth with regionally specific volumetric changes, sensory processing dysregulation, and repetitive behavior abnormalities. Prior rapamycin studies in autism models focused on chronic treatments that alter or prevent physical brain changes. Here, we focus on acute rapamycin effects to uncover novel mTOR pathway-mediated mechanisms of dysfunction. Within 2 hours, rapamycin rescues neuronal hyperexcitability, seizure susceptibility, functional network connectivity, brain community structure, repetitive behaviors, and sensory over-responsivity in adult MIR offspring. These CNS-mediated effects coincide with altered expression of genes associated with ASD, ion channels, and epilepsy. Our findings demonstrate that mTOR dysregulation drives dysfunctional brain development in MIR offspring but the adult brain remains amenable to rapid functional normalization, rescuing core and comorbid ASD-associated brain and behavior phenotypes. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing multiple ASD phenotypes.</p>

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Acute rapamycin treatment reveals distinct mechanisms of dysfunction in a maternal inflammation mouse model

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月23日

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  • JE Le Belle,
  • M. C. Condro,
  • C. Cepeda,
  • KD Oikonomou,
  • K. Tessema,
  • L. Dudley,
  • J. Schoenfield,
  • R. Kawaguchi,
  • D. Geschwind,
  • AJ Silva,
  • Z. Zhang,
  • K. Shokat,
  • NG Harris,
  • HI Kornblum

摘要

Maternal inflammatory response (MIR) during early mouse gestation induces a cascade of physiological and behavioral changes associated with autism spectrum disorder (ASD). We have shown that mild MIR causes chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth with regionally specific volumetric changes, sensory processing dysregulation, and repetitive behavior abnormalities. Prior rapamycin studies in autism models focused on chronic treatments that alter or prevent physical brain changes. Here, we focus on acute rapamycin effects to uncover novel mTOR pathway-mediated mechanisms of dysfunction. Within 2 hours, rapamycin rescues neuronal hyperexcitability, seizure susceptibility, functional network connectivity, brain community structure, repetitive behaviors, and sensory over-responsivity in adult MIR offspring. These CNS-mediated effects coincide with altered expression of genes associated with ASD, ion channels, and epilepsy. Our findings demonstrate that mTOR dysregulation drives dysfunctional brain development in MIR offspring but the adult brain remains amenable to rapid functional normalization, rescuing core and comorbid ASD-associated brain and behavior phenotypes. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing multiple ASD phenotypes.