ER stress-induced modulation of neural activity and seizure susceptibility is impaired in a fragile X syndrome mouse model

Neurobiol Dis. 2021 Oct;158:105450. doi: 10.1016/j.nbd.2021.105450. Epub 2021 Jul 23.

Abstract

Imbalanced neuronal excitability homeostasis is commonly observed in patients with fragile X syndrome (FXS) and the animal model of FXS, the Fmr1 KO. While alterations of neuronal intrinsic excitability and synaptic activity at the steady state in FXS have been suggested to contribute to such a deficit and ultimately the increased susceptibility to seizures in FXS, it remains largely unclear whether and how the homeostatic response of neuronal excitability following extrinsic challenges is disrupted in FXS. Our previous work has shown that the acute response following induction of endoplasmic reticulum (ER) stress can reduce neural activity and seizure susceptibility. Because many signaling pathways associated with ER stress response are mediated by Fmr1, we asked whether acute ER stress-induced reduction of neural activity and seizure susceptibility are altered in FXS. Our results first revealed that acute ER stress can trigger a protein synthesis-dependent prevention of neural network synchronization in vitro and a reduction of susceptibility to kainic acid-induced seizures in vivo in wild-type but not in Fmr1 KO mice. Mechanistically, we found that acute ER stress-induced activation of murine double minute-2 (Mdm2), ubiquitination of p53, and the subsequent transient protein synthesis are all impaired in Fmr1 KO neurons. Employing a p53 inhibitor, Pifithrin-α, to mimic p53 inactivation, we were able to blunt the increase in neural network synchronization and reduce the seizure susceptibility in Fmr1 KO mice following ER stress induction. In summary, our data revealed a novel cellular defect in Fmr1 KO mice and suggest that an impaired response to common extrinsic challenges may contribute to imbalanced neuronal excitability homeostasis in FXS.

Keywords: ER stress; FMRP; FXS; Hyperexcitability; Seizures.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiazoles / pharmacology
  • Endoplasmic Reticulum Stress / genetics*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / genetics*
  • Genetic Predisposition to Disease / genetics
  • Kainic Acid
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Net / physiopathology
  • Patch-Clamp Techniques
  • Seizures / chemically induced
  • Seizures / genetics*
  • Seizures / physiopathology
  • Toluene / analogs & derivatives
  • Toluene / pharmacology
  • Tumor Suppressor Protein p53 / antagonists & inhibitors

Substances

  • Benzothiazoles
  • Fmr1 protein, mouse
  • Tumor Suppressor Protein p53
  • Fragile X Mental Retardation Protein
  • Toluene
  • pifithrin
  • Kainic Acid