第一介白素受體在小鼠癲癇誘發之睡眠障礙中所扮演的角色

Abstract

癲癇與睡眠障礙經常相互伴隨而影響，然而對於癲癇誘發睡眠障礙的相關機制仍有待釐清。第一介白素 (interleukin-1) 為重要睡眠調節物質 (sleep regulatory substances; SRSs) 之一，且已被證實於病理性傷害時濃度會大量上升。先前實驗室實驗已證實不同 zeitgeber time (ZT) 發作之癲癇對於睡眠的改變也不相同，且第一介白素在 ZT13 癲癇導致之睡眠改變中具有一定重要性。故本實驗探討第一介白素第一型受體之剔除 (IL-1R1 knockout; IL-1R1 +/- & -/-) 是否能夠影響癲癇誘發的閾值，及探討 ZT13 癲癇發作後第一介白素之濃度改變與睡眠障礙之關聯性。 實驗方法利用 IL-1R1 knockout 之小鼠，手術植入腦波圖電極於腦皮質表面，另一雙極性電極植入於左側杏仁核之底側核 (basolateral nucleus of amygdala)。紀錄腦波圖，並與wildtype小鼠比較其正常睡眠之變化。以 rapid electrical amygdala kindling model (REAK) 誘發癲癇形成並探討第一介白素於癲癇誘發中扮演的角色。隔日給予電刺激誘發ZT13癲癇，紀錄睡眠腦波圖之改變，並比較IL-1R1 knockout小鼠與wildtype小鼠之異常以探討第一介白素對癲癇誘發睡眠改變之影響。 IL-1R1 knockout小鼠與wildtype小鼠間之癲癇閾值改變並無統計上顯著意義。在正常睡眠周期， IL-1R1 -/- 小鼠的黑暗期非快速動眼期睡眠 (non-rapid eye movement sleep; non-REM sleep; NREM sleep) 較 wildtype 小鼠與 IL-1R1 +/- 小鼠顯著升高，而快速動眼期睡眠則依wildtype、IL-1R1 +/-、IL-1R1 -/- 小鼠依序顯著下降。誘發ZT13癲癇後， wildtype 小鼠於癲癇後六小時內 NREM sleep 顯著上升，但在 IL-1R1 knockout小鼠則皆無NREM sleep的顯著改變，故推測 IL-1 R1 對 ZT13 癲癇發作後睡眠的改變中扮演重要角色。 本實驗證明 IL-1R1小鼠對癲癇誘發閾值的改變較無顯著作用，但對癲癇誘發後之睡眠障礙扮演非常重要之角色。

Epilepsy and sleep are very closely related, but the mechanisms behind epilepsy-induced sleep disturbances are yet to be completely clarified. Interleukin-1 (IL-1), a sleep regulatory substance (SRS), is evidenced to participate in many pathological sleep changes. Our previous studies have demonstrated that seizure occurred at different zeitgeber time (ZT) alters sleep differently and IL-1 mediates the sleep alterations induced by ZT13 epilepsy. In this study, we determined the role of IL-1 type 1 receptor (IL-1R1) in epileptogenesis and in epilepsy-induced sleep disruptions using IL-1R1 homozygous and heterozygous knockout (IL-1R1 -/- and +/-) mice. Mice were surgically implanted with electroencephalogram (EEG) electrodes to record the sleep-wake activities. The difference of undisturbed sleep among wildtype and IL-1R1 knockout mice were obtained to evaluate the importance of IL-1R1 in sleep regulation. Rapid electrical amygdala kindling (REAK) was performed to induce epilepsy at a particular zeitgeber time (ZT), ZT13, and to determine the role of IL-1R1 in epileptogenesis. Sleep-wake activities before and after ZT13 kindling stimulation were acquired to evaluate the role of IL-1R1 in epilepsy-induced sleep alterations by comparing the difference between wildtype and IL-1R1 knockout mice. The difference of seizure threshold indicators, such as the after-discharge threshold (ADT), a successful kindling rate and Racine’s stage seizures, were not significantly altered among wildtype, IL-1R1 +/- and IL-1R -/- mice, suggesting the lesser significance of IL-1R1 in epileptogenesis. Non-rapid eye movement (non-REM; NREM) sleep obtained from IL-1R1 -/- mice during the dark period (ZT13-24) was significantly higher than that acquired from wildtype and IL-1R1 +/- mice, and REM sleep declined in both IL-1R1 +/- and IL-1R1 -/- mice during the light period (ZT’1-12). ZT13 kindling stimulation significantly enhanced NREM sleep during the subsequent 6 hours (ZT13-18) and decreased NREM sleep during ZT23-24 in wildtype mice. These sleep alterations, however, were not exhibited in either IL-1R1 +/- or IL-1R -/- mice. This study demonstrated that IL-1R1 may have a diminutive role in epileptogenesis, but plays an important role in modulating epilepsy-induced sleep disturbances.