12432 Chronic Intermittent Hypoxia Impairs Calpain And Caspase-3 Activity In The Hippocampus

Abstract Disclosure: S. Mabry: None. J.L. Bradshaw: None. J.J. Gardner: None. E.N. Wilson: None. H. Yeung: None. R.L. Cunningham: None. Background: Obstructive sleep apnea (OSA) is a highly prevalent sleeping disorder in the USA with known sex differences in incidence and severity. OSA is associated with memory impairments. However, the mechanisms by which OSA disrupts memory are not fully understood. Calpain and caspase-3 are proteases which regulate synaptic function and memory formation and have been observed to be sensitive to gonadal hormone levels (testosterone, estradiol). OSA has been observed to decrease gonadal hormones. This study examined whether chronic intermittent hypoxia (CIH), a rat model of OSA: (1) induced dysregulation in calpain and caspase-3 activity in the dorsal hippocampus; (2) if these proteases were dependent on circulating gonadal hormones; and (3) if these effects were dependent on sex. Methods: Adult Sprague-Dawley male and female rats were exposed to CIH or normoxic room-air for 14 days. At the conclusion of CIH, rats were sacrificed, and tissues were collected. Plasma was collected to measure circulating gonadal hormones (testosterone, estradiol). Gonadal hormones were extracted from the plasma and analyzed by high throughput multiplex. Brains were flash frozen and dissected for hippocampal subregion isolation. We quantified calpain and caspase-3 cleavage activity by measuring cleaved spectrin within CA1 and CA3 subregions of the dorsal hippocampus. Results: CIH impaired calpain cleavage activity in the CA1 of males, with no effect on calpain activity in the CA1 of females. No effects of CIH or sex on caspase-3 cleavage activity were observed in the CA1. In contrast, caspase-3 cleavage activity was reduced by CIH in the CA3 in females but not males. No effects of CIH or sex were observed on calpain cleavage activity in the CA3. No effects of CIH were observed on gonadal hormones. We observed expected sex differences in testosterone (males higher than females) and estradiol (no sex difference between males and females). Conclusions: Our results indicate that CIH impairs calpain and caspase-3 cleavage activity in a hippocampal subregion- and sex-specific manner. These effects were independent of circulating gonadal hormones. Since the CA1 and CA3 subregions of the dorsal hippocampus are involved in memory consolidation, these cellular changes in calpain and caspase-3 activity could mediate CIH-induced memory impairments, such as impaired recollective memory. These findings could have clinical implications for memory impairments in patients with OSA. Presentation: 6/2/2024