Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/ijms19092811
Keywords
ATR-X syndrome; cognitive function; dendritic spine; sigma-1 receptor; brain-derived neurotrophic factor
Funding
- Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED)
- MEXT/JSPS KAKENHI [25110705]
- KAKENHI [24659024]
- Grants-in-Aid for Scientific Research [24659024, 25110705] Funding Source: KAKEN
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alpha-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.
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