Dravet Syndrome (DS) is caused by heterozygous loss-of-function mutations in voltage-gated sodium channel NaV1.1. Our genetic mouse model of DS recapitulates its severe seizures and premature death. Sleep disturbance is common in DS, but its mechanism is unknown. Electroencephalographic studies revealed abnormal sleep in DS mice, including reduced delta wave power, reduced sleep spindles, increased brief wakes, and numerous interictal spikes in Non-Rapid-Eye-Movement sleep. Theta power was reduced in Rapid-Eye-Movement sleep. Mice with NaV1.1 deleted specifically in forebrain interneurons exhibited similar sleep pathology to DS mice, but without changes in circadian rhythm. Sleep architecture depends on oscillatory activity in the thalamocortical network generated by excitatory neurons in the ventrobasal nucleus (VBN) of the thalamus and inhibitory GABAergic neurons in the reticular nucleus of the thalamus (RNT). Whole-cell NaV current was reduced in GABAergic RNT neurons but not in VBN neurons. Rebound firing of action potentials following hyperpolarization, the signature firing pattern of RNT neurons during sleep, was also reduced. These results demonstrate imbalance of excitatory vs. inhibitory neurons in this circuit. As predicted from this functional impairment, we found substantial deficit in homeostatic rebound of slow wave activity following sleep deprivation. Although sleep disorders in epilepsies have been attributed to anti-epileptic drugs, our results show that sleep disorder in DS mice arises from loss of NaV1.1 channels in forebrain GABAergic interneurons without drug treatment. Impairment of NaV currents and excitability of GABAergic RNT neurons are correlated with impaired sleep quality and homeostasis in these mice.

Periodic ovulation in rats, mice and hamsters is the result of a surge in LH that depends on circadian gating signals emerging from the master circadian clock within the suprachiasmatic nucleus (SCN) and rising ovarian oestrogen levels. These two signals converge into the anteroventral periventricular nucleus (AVPV) and lead to the release of kisspeptin, which is responsible for surges of GnRH and, in turn, of LH release. How the AVPV integrates circadian and reproductive signals remains unclear. Here we show that the female rat AVPV itself shows circadian oscillations in the expression of the clock genes PER1 and BMAL1, which lie at the core circadian clockwork of mammals. In ovariectomized (OVX) females treated with estradiol (E2) these oscillations are in synchrony with the AVPV rhythmic expression of the KISS1 gene and the gene that codes for the arginine-vasopressin (AVP) receptor AVPr1a. Whereas clock gene oscillations are independent of oestrogen levels, circadian expression of Kiss1 and Avpr1a (also referred to as V1a) mRNA are respectively blunted and absent in ovariectomized animals without E2 replacement. Because AVP is believed to be a critical SCN transmitter to gate the LH surge, our data suggest that a there is a circadian oscillator located in the AVPV, and that such a putative oscillator could time, in an oestrogen dependent manner, the sensitivity to circadian signals emerging from the SCN and the release of kisspeptin.

These experiments identify a novel role for PER2 during a midazolam- or constant light-induced delirium-like state, highlight the importance of hippocampal PER2 expression for cognitive function, and suggest the PER2 enhancer nobiletin as potential therapy in delirium-like conditions associated with circadian disruption.

The most dramatic feature of life on Earth is our adaptation to the cycle of day and night. Throughout evolutionary time, almost all living organisms developed a molecular clock linked to the light-dark cycles of the sun. In present time, we know that this molecular clock is crucial to maintain metabolic and physiological homeostasis. Indeed, a dysregulated molecular clockwork is a major contributing factor to many metabolic diseases. In fact, the time of onset of acute myocardial infarction exhibits a circadian periodicity and recent studies found that the light regulated circadian rhythm protein Period 2 (PER2) elicits endogenous cardioprotection from ischemia. Manipulating the molecular clockwork may prove beneficial during myocardial ischemia in humans. MicroRNAs are small non-coding RNA molecules capable of silencing messenger RNA (mRNA) targets. MicroRNA dysregulation has been linked to cancer development, cardiovascular and neurological diseases, lipid metabolism, and impaired immunity. Therefore, microRNAs are gaining interest as putative novel disease biomarkers and therapeutic targets. To identify circadian microRNA-based cardioprotective pathways, a recent study evaluated transcriptional changes of PER2 dependent microRNAs during myocardial ischemia. Out of 352 most abundantly expressed microRNAs, miR-21 was amongst the top PER2 dependent microRNAs and was shown to mediate PER2 elicited cardioprotection. Further analysis suggested circadian entrainment via intense light therapy to be a potential strategy to enhance miR-21 activity in humans. In this review, we will focus on circadian microRNAs in the context of cardioprotection and will highlight new discoveries, which could lead to novel therapeutic concepts to treat myocardial ischemia.