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.
Highlights
Several ATRX mutations or low ATRX gene expression have been identified in patients with ATR-X syndrome [8,9,10,11]
As dendritic spines originate from dendritic filopodia, we hypothesized that Atrx∆E2 neurons change the development of these structures
The number of filopodia was significantly increased in cultured neurons of Atrx∆E2 mice relative to the number measured in WT mice (Figure 1C), and cultured neurons from Atrx∆E2 mice treated with SA4503 showed a significant decrease in the number of filopodia (Figure 1A4,C) (The number of filopodia per 20 μm dendritic length; WT + vehicle, 2.1 ± 0.3; WT + SA4503, 2.1 ± 0.4; Atrx∆E2 + vehicle, 7.7 ± 0.4; Atrx∆E2 + SA4503, 3.8 ± 0.4)
Summary
Several ATRX mutations or low ATRX gene expression have been identified in patients with ATR-X syndrome [8,9,10,11]. The volume of the spine head is directly proportional to the area of postsynaptic density and the number of postsynaptic receptors, and, the size of synaptic currents and synaptic strength [19,20,21,22]. Such spine anomalies have been reported in several neurological disorders associated with cognitive dysfunction, including Alzheimer’s diseases, schizophrenia, and intellectual disability [17,18,23,24]. We show that Sig-1R activation with SA4503, a potent activator of Sig-1R [32], features potential as a therapeutic intervention for diminished cognitive function in ATR-X syndrome
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