OBJECTIVE/BACKGROUND: This study aimed to investigate the role of astrocyte activation in cognitive dysfunction induced by chronic intermittent hypoxia (CIH) in juvenile rats, along with the underlying mechanisms and related molecular targets.

METHODS

A total of 40 postnatal day 18 Sprague-Dawley rats were randomized into four groups (n = 10/group): control, CIH, vehicle, and CIH + iβARK group. The CIH model was established by exposing rats to intermittent hypoxia for 8 h daily (7 %-21 %) for 4 weeks. Four days before hypoxia exposure, AAV5-GfaABC1D-iβARK-p2A-mCherry (viral titer:2.60E+12) was stereotactically injected into the bilateral lateral ventricles (2 μl per ventricle) (coordinates: AP -0.8 mm, ML ±1.5 mm, DV -3.6 mm relative to bregma). After hypoxia ends, rat learning and memory were assessed using the water maze (n = 6/group), the activity of astrocytes was detected by immunofluorescence, morphological changes in hippocampal and dendritic spines were examined using HE staining and Golgi staining (n = 3/group), and the expressions of SYP, PSD - 95, Hevin, TSP - 1 and PI3K - AKT - mTOR were detected by western blotting and Q-PCR (n = 3/group).

RESULTS

Compared with the Control group (14.83 ± 1.17 s), rats in the CIH group spent more time locating the escape platform (19.67 ± 3.33 s, p < 0.05), with a decrease in the number of platform explorations and crossings (5.00 ± 0.89 vs 2.33 ± 0.82, p < 0.001). In the CA1 region of the hippocampus, neuronal degeneration and a reduction in dendritic spine density (6.65 ± 1.03 vs 4.08 ± 1.02, p < 0.05) were noted. The expression levels of SYP(1.00 ± 0.05 vs 0.44 ± 0.05,p < 0.001), PSD - 95 (1.00 ± 0.08 vs 0.46 ± 0.06,p < 0.001), Hevin (1.00 ± 0.11 vs 0.44 ± 0.12,p < 0.01), and TSP - 1 (1.00 ± 0.02 vs 0.49 ± 0.02,p < 0.0001), as well as the ratios of p - PI3K/PI3K(1.00 ± 0.10 vs 0.09 ± 0.15, p < 0.001), p - AKT/AKT (1.00 ± 0.02 vs 0.44 ± 0.06, p < 0.01), and p - mTOR/mTOR (1.00 ± 0.05 vs 0.58 ± 0.08, p < 0.001), decreased. Nevertheless, in the CIH + iβARK group with inhibited astrocyte activity, all these changes were reversed, and the differences were statistically significant.

CONCLUSIONS

Astrocyte activation was closely associated with CIH - induced cognitive dysfunction in juvenile rats. The underlying mechanism may be linked to decreased expression of synapse-related proteins and reduced dendritic spine density. Inhibiting astrocyte activation could alleviate synaptic dysfunction and cognitive decline in juvenile rats. This finding may provide a direction for exploring new treatment strategies for cognitive impairments related to obstructive sleep apnea in children.