Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking

Hannibal, Jens; Brabet, Philippe; Fahrenkrug, Jan

doi:10.1152/ajpregu.90563.2008

Cited by 45 publications

(57 citation statements)

References 30 publications

(48 reference statements)

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“…Our negative masking experiments show that Scn1a +/− mice are more sensitive to light than WT mice. Genetic mutations that affect retinal sensitivity usually cause both reduced light-induced phase shifts and diminished negative masking (47,48). Our results show that circadian photoresponsiveness and negative masking can be affected in opposite directions in an animal with intact retinal photoreception.…”

Section: Discussionmentioning

confidence: 68%

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Han

Yu²,

Schwartz³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Na V 1.1 is the primary voltage-gated Na + channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na V 1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a +/− ), which encodes the pore-forming α-subunit of the Na V 1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a +/− mice have exaggerated light-induced negativemasking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a +/− mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a +/− mice, and this communication is barely detectable in the homozygous gene KO (Scn1a −/− ). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na V 1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na + channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na V 1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients. entrainment | neuronal oscillators | sodium channel T he mammalian suprachiasmatic nucleus (SCN) of the hypothalamus houses a master circadian clock that governs phase coordination between peripheral oscillators and overt circadian rhythms (1) as well as synchronization of these rhythms to the light-dark (LD) cycle through the retinohypothalamic tract (RHT) (2). Although SCN neurons are autonomous single-cell oscillators that rely on autoregulatory transcriptional/translational feedback loops of clock genes (3, 4), interneuronal synchronization is critical for the SCN to act as a tissue pacemaker with a coherent output (5, 6). Sodium-dependent action potentials are known to be essential for the synchronization between clock neurons in the SCN as well as necessary to maintain robust oscillations of clock gene expression (ref. 7 and reviewed in ref. 6), but the molecular identity of voltage-gated Na + channels contributing to the synchronization of the SCN neuronal network is currently unknown.Over 90% of SCN neurons contain GABA as a neurotransmitter and express GABA A and GABA B receptors (8-10), and electrophysiological and pharmacological studies in vitro have pointed to GABA as a key signal mediating SCN neuronal network properties (11,12). Studies of mutant mice show that voltage-gated sodium channel type 1 (Na V 1.1) encoded by the Scn1a gene is the primary voltage-gated Na + channel in...

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Section: Discussionmentioning

confidence: 68%

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Han

Yu²,

Schwartz³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Light induced phase shift of the circadian rhythm was determined using the Aschoff type II regime as described previously [39]. All animals were light stimulated for 30 min at 300 lux in their home-cages in separate experiments at ZT16 and ZT22, respectively, where after the lights were turned off for the next 10–14 d followed by 14 d of re-entrainment in LD before the next light pulse experiment.…”

Section: Methodsmentioning

confidence: 99%

Circadian Behaviour in Neuroglobin Deficient Mice

et al. 2012

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Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night.

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“…Furthermore, light stimulation at early night results in a larger phase delay in PAC1-R knockout mice than in wild-type animals (Hannibal et al, 2001a). However, subsequent examination of PAC1-R knock-out mice under the more natural Ashoff II light stimulation regime disclosed a significantly decreased phase delay of the endogenous rhythm at early night (Hannibal et al, 2008). At late night, the phase advance observed after light stimulation was attenuated in PACAP(Ϫ/Ϫ) mice Colwell et al, 2004;Fahrenkrug et al, 2005;Beaulé et al, 2009) and converted into a phase delay in PAC1-R knockout animals (Hannibal et al, 2001a).…”

Section: Actions Of Pituitary Adenylate Cyclase-activating Polypeptidmentioning

confidence: 97%

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

et al. 2009

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Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking

Abstract: Hannibal J, Brabet P, Fahrenkrug J. Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking.

Cited by 45 publications

References 30 publications

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Circadian Behaviour in Neuroglobin Deficient Mice

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

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Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking

Abstract: Hannibal J, Brabet P, Fahrenkrug J. Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking.

Cited by 45 publications

References 30 publications

Na V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Na V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Circadian Behaviour in Neuroglobin Deficient Mice

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

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Product

Resources

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Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms