Abstract
BackgroundThe astroglial connexins Cx30 and Cx43 contribute to many important CNS functions including cognitive behaviour, motoric capacity and regulation of the sleep-wake cycle. The sleep wake cycle, is controlled by the circadian system. The central circadian rhythm generator resides in the suprachiasmatic nucleus (SCN). SCN neurons are tightly coupled in order to generate a coherent circadian rhythm. The SCN receives excitatory glutamatergic input from the retina which mediates entrainment of the circadian system to the environmental light-dark cycle. Connexins play an important role in electric coupling of SCN neurons and astrocytic-neuronal signalling that regulates rhythmic SCN neuronal activity. However, little is known about the regulation of Cx30 and Cx43 expression in the SCN, and the role of these connexins in light entrainment of the circadian system and in circadian rhythm generation.MethodsWe analysed time-of-day dependent as well as circadian expression of Cx30 and Cx43 mRNA and protein in the mouse SCN by means of qPCR and immunohistochemistry. Moreover, we analysed rhythmic spontaneous locomotor activity in mice with a targeted deletion of Cx30 and astrocyte specific deletion of Cx43 (DKO) in different light regimes by means of on-cage infrared detectors.ResultsFluctuation of Cx30 protein expression is strongly dependent on the light-dark cycle whereas fluctuation of Cx43 protein expression persisted in constant darkness. DKO mice entrained to the light-dark cycle. However, re-entrainment after a phase delay was slightly impaired in DKO mice. Surprisingly, DKO mice were more resilient to chronodisruption.ConclusionCircadian fluctuation of Cx30 and Cx43 protein expression in the SCN is differently regulated. Cx30 and astroglial Cx43 play a role in rhythm stability and re-entrainment under challenging conditions.
Highlights
Gap junctions represent direct cell-to-cell communications, which allow trafficking of a wide variety of small molecules (< 1.5 kDa) including ions, neurotransmitters, and metabolites such as glucose between the cytoplasm of adjacent cells, and regulating intercellular metabolic and electric coupling
Expression of Cx30 and Cx43 mRNA in the suprachiasmatic nucleus (SCN) exhibits a time-of-day-dependent variation with a peak during the early dark phase. This fluctuation was absent when the mice were kept in constant darkness, suggesting that rhythmic expression of Cx30 and Cx43 mRNA is driven by the light/dark cycle
Cx30 and Cx43 mRNA relative expression levels under different light conditions In the SCN of C57Bl/6 mice kept in 12:12 LD, Cx30 (Fig. 1a) and Cx43 (Fig. 1b) mRNA relative expression levels were significantly higher during the early dark phase (ZT14) as compared to the late dark phase (ZT22)
Summary
Gap junctions represent direct cell-to-cell communications, which allow trafficking of a wide variety of small molecules (< 1.5 kDa) including ions, neurotransmitters, and metabolites such as glucose between the cytoplasm of adjacent cells, and regulating intercellular metabolic and electric coupling. To determine the role of interastrocytic coupling for entrainment and circadian rhythm generation and stability, we analysed spontaneous locomotor activity in a jet lag paradigm, in constant darkness (DD) and in a paradigm for chronodisruption (constant light) in Cx30- and astroglial-specific Cx43 double knockout mice (DKO). Expression of Cx30 and Cx43 mRNA in the SCN exhibits a time-of-day-dependent variation with a peak during the early dark phase This fluctuation was absent when the mice were kept in constant darkness, suggesting that rhythmic expression of Cx30 and Cx43 mRNA is driven by the light/dark cycle. Little is known about the regulation of Cx30 and Cx43 expression in the SCN, and the role of these connexins in light entrainment of the circadian system and in circadian rhythm generation
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