SA4503, A potent sigma-1 receptor ligand, ameliorates synaptic abnormalities and cognitive dysfunction in a mouse model of ATR-X syndrome

Kouya Yamaguchi, Norifumi Shioda, Yasushi Yabuki, Chen Zhang, Feng Han, Kohji Fukunaga

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

α-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX. An ATR-X model mouse lacking Atrx exon 2 displays phenotypes that resemble symptoms in the human intellectual disability: cognitive defects and abnormal dendritic spine formation. We herein target activation of sigma-1 receptor (Sig-1R) that can induce potent neuroprotective and neuroregenerative effects by promoting the activity of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). We demonstrated that treatment with SA4503, a potent activator of Sig-1R, reverses axonal development and dendritic spine abnormalities in cultured cortical neurons from ATR-X model mice. Moreover, the SA4503 treatment rescued cognitive deficits exhibited by the ATR-X model mice. We further found that significant decreases in the BDNF-protein level in the medial prefrontal cortex of ATR-X model mice were recovered with treatment of SA4503. These results indicate that the rescue of dendritic spine abnormalities through the activation of Sig-1R has a potential for post-diagnostic therapy in ATR-X syndrome.

Original languageEnglish
Article number2811
JournalInternational journal of molecular sciences
Volume19
Issue number9
DOIs
Publication statusPublished - 2018 Sep 18

Keywords

  • ATR-X syndrome
  • Brain-derived neurotrophic factor
  • Cognitive function
  • Dendritic spine
  • Sigma-1 receptor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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