Effects of ADAM10 inhibitor on synaptic structure and blood-brain barrier permeability in rats with autism-like behavior

Abstract

Objective To investigate the effects of a disintegrin and metalloprotease domain 10 (ADAM10) inhibitor on synaptic structure and blood-brain barrier (BBB) permeability in rats with autism-like behavior. Methods A total of 50 male offspring rats with prenatal exposure to valproic acid (VPA) to induce autism-like behavior were randomly divided into VPA group and ADAM10 inhibitor, TAT-Pro-ADAM10 (709-729) group (TAT-Pro group), with 25 rats in each group. And another 25 offspring male rats induced by normal saline during pregnancy served as control group (CON group). The TAT-Pro group was given intraperitoneal injection on postnatal day 20 with 3 nmol/g TAT-Pro-ADAM10 (709-729), and equal volumes of normal saline were given to the CON and VPA groups. The changes of body mass and tail length of offspring rats were measured and recorded during modeling. Western blotting was performed to detect the protein levels of ADAM10, vascular endothelial cadherin (VE-Cad), Occludin, zonula occludens-1 (ZO-1), post-synaptic density protein-95 (PSD95), and synaptophysin (SYN) in the hippocampal tissue of the offspring rats in 24 h after administration. The expression of ZO-1 protein was further verified by immunofluorescence assay. Behavioral tests were conducted from postnatal day 24, including open field, grooming, three-chamber social interaction, and water maze tests. The density of dendritic spines in hippocampal tissue in the offspring rats on postnatal day 28 was detected by Golgi staining. Results Compared with the VPA group, the TAT-Pro group showed no significant changes in body weight and tail length, but significantly improved repetitive stereotyped behaviors, social skills and learning memory ability (P < 0.05), reduced protein levels of ADAM10 and PSD95 in hippocampal tissues (P < 0.05), and elevated levels of VE-cad and Occludin (P < 0.05). The density of dendritic spines was significantly reduced (P < 0.05), and the number of immature dendritic spines also decreased in the TAT-Pro group than the VPA group. Conclusion Inhibition of ADAM10 overexpression during the critical period of synaptic development can alleviate learning and memory dysfunctions in VPA-induced rats with autism-like behavior, and has a certain restorative effect on abnormal synaptic structures and blood-brain barrier permeability.

Keywords

• autism spectrum disorder
• a disintegrin and metalloprotease domain 10
• blood-brain barrier
• synapsis