Rationale:
Chronic intermittent hypoxia (CIH) is the most distinct feature of obstructive sleep apnea (OSA), a very common breathing and sleep disorder, that leads to several neuropathological consequences, including alterations in the hippocampal network and in the susceptibility to seizures. However, it is unknown whether these alterations are permanent or do remit upon normal oxygenation.
Methods:
Adult male Wistar rats were daily given intermittent hypoxia for 21 days (5% 02 / 95% CO2; 8 hours/day), by using Plexiglas chambers equipped with gas injectors and O2, CO2, humidity and temperature sensors. To investigate the reversibility of the CIH effects, animals were submitted to the CIH protocol followed by 30 days of reoxygenation (ReOx), while animals breathed normoxic room air (20% 02 / 80% N2). Each CIH animal group was matched with a littermate control group (CTL), which were simultaneously introduced, in collective cages (4 animals / cage), into the same Plexiglas chambers but breathed normoxic air. At the end of CIH or CIH+ReOx protocols, hippocampal slices were obtained. Local field potentials from the CA1-stratum pyramidale were recorded before (basal) and during 4-aminopyridine (4AP; 100µM)-induced epileptiform activity. Experimental procedures were carried out in accordance with the Official Mexican Norm published by Mexico's Ministry of Agriculture (SAGARPA NOM-062-ZOO-1999), which complies with the guidelines of the Institutional Animal Care and Use Committee Guidebook (NIH publication 80-23, Bethesda, MD, 1996).
Results:
We found that application of CIH to adult rats increases relative power of the gamma band (30-115 Hz) during basal hippocampal network activity (p<0.05) while aggravates 4AP-induced epileptiform activity in vitro (p<0.001 vs control). Interestingly, these CIH-induced alterations are reverted after 30-d of normal oxygenation (p>0.1 vs control).
Conclusions:
Our findings indicate that CIH-induced hippocampal network alterations and increased seizure susceptibility are not permanent and can be spontaneously reverted, suggesting that therapeutic interventions against OSA in patients with epilepsy, such as surgery or continuous positive airway pressure, could result in favorable effects in seizures control.
Funding: Benjamín Villasana-Salazar and Rebeca Hernández-Soto are doctoral students from “Programa de Doctorado en Ciencias Biomédicas” at “Universidad Nacional Autónoma de México” (UNAM) and have received fellowships (No. 587113 and 612139, respectively) from “Consejo Nacional de Ciencia y Tecnología” (CONACyT), México. María Estefanía Guerrero-Gómez received a Research Assistant fellowship (No. 15650) from “Sistema Nacional de Investigadores” (SNI), CONACyT, México. This work was supported by “Dirección General de Asuntos del Personal Académico”, UNAM, México (grant number IN202018).