In mammals, the precise circadian timing of many biological processes depends on the generation of oscillations in neural activity of pacemaker cells in the suprachiasmatic nucleus (SCN) of the hypothalamus. Understanding the ionic mechanisms underlying these rhythms is an important goal of research in chronobiology. Previous work has shown that SCN neurons express A-type potassium currents (IAs), but little is known about the properties of this current in the SCN. We sought to characterize some of these properties, including the identities of IA channel subunits found in the SCN and the circadian regulation of IA itself. In this study, we were able to detect significant hybridization for Shal-related family members 1 and 2 (Kv4.1 and 4.2) within the SCN. In addition, we used Western blot to show that the Kv4.1 and 4.2 proteins are expressed in SCN tissue. We further show that the magnitude of the IA current exhibits a diurnal rhythm that peaks during the day in the dorsal region of the mouse SCN. This rhythm seems to be driven by a subset of SCN neurons with a larger peak current and a longer decay constant. Importantly, this rhythm in neurons in the dorsal SCN continues in constant darkness, providing an important demonstration of the circadian regulation of an intrinsic voltage-gated current in mammalian cells. We conclude that the anatomical expression, biophysical properties, and pharmacological profiles measured are all consistent with the SCN IA current being generated by Kv4 channels. Additionally, these data suggest a role for IA in the regulation of spontaneous action potential firing during the transitions between day/night and in the integration of synaptic inputs to SCN neurons throughout the daily cycle.
"The regulation of action potential frequency in SCN neurons is controlled by a number of ionic channels, among them two circadian controlled K + conductances, which we recently studied in old mice (Fig. 3; Farajnia and others 2012). The fast delayed rectifier K + current (Itri and others 2005) and also the transient K + current (Itri and others 2010) lost their circadian modulation in old SCN neurons, which is consistent with the diminished rhythm in neuronal activity (Fig. 2E). Importantly, not all ionic currents were affected by age. "
[Show abstract][Hide abstract] ABSTRACT: More than half of the elderly in today's society suffer from sleep disorders with detrimental effects on brain function, behavior, and social life. A major contribution to the regulation of sleep stems from the circadian system. The central circadian clock located in the suprachiasmatic nucleus of the hypothalamus is like other brain regions subject to age-associated changes. Age affects different levels of the clock machinery from molecular rhythms, intracellular messenger, and membrane properties to neuronal network synchronization. While some of the age-sensitive components of the circadian clock, like ion channels and neurotransmitters, have been described, little is known about the underlying mechanisms. In any case, the result is a reduction in the amplitude of the circadian timing signal produced by the suprachiasmatic nucleus, a weakening in the control of peripheral oscillators and a decrease in amplitude and precision of daily rhythms in physiology and behavior. The distortion in temporal organization is thought to be related to a number of serious health problems and promote neurodegeneration. Understanding the mechanisms underlying age-related deficits in circadian clock function will therefore not only benefit rhythm disorders but also alleviate age-associated diseases aggravated by clock dysfunction.
The Neuroscientist 08/2013; 20(1). DOI:10.1177/1073858413498936 · 6.84 Impact Factor
"Exactly how the transcriptional/translational molecular clock operates on neurophysiological changes is not well understood (Ko et al., 2009; Colwell, 2011), but is believed to involve intercellular coupling of these cellular processes with synchronization of neuronal networks (Mohawk and Takahashi, 2011). Circadian modulation of action potential firing rates (Green and Gillette, 1982; Cutler et al., 2003; Atkinson et al., 2011) and amplitude (Belle et al., 2009) are known to exist, and include changes in the activity of ion channels, such as the fast-delayed rectifier (Itri et al., 2005), BK-channel induced calcium-activated potassium current (Kent and Meredith, 2008), and the A-type potassium currents (Itri et al., 2010). Changes in SCN neurophysiology has been shown to regulate gene expression, since blockage of firing using TTX has been shown to reduce the amplitude of Period transcript levels (Yamaguchi et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Evolutionarily, what was the earliest engram? Biology has evolved to encode representations of past events, and in neuroscience, we are attempting to link experience-dependent changes in molecular signaling with cellular processes that ultimately lead to behavioral output. The theory of evolution has guided biological research for decades, and since phylogenetically conserved mechanisms drive circadian rhythms, these processes may serve as common predecessors underlying more complex behavioral phenotypes. For example, the cAMP/MAPK/CREB cascade is interwoven with the clock to trigger circadian output, and is also known to affect memory formation. Time-of-day dependent changes have been observed in long-term potentiation (LTP) within the suprachiasmatic nucleus and hippocampus, along with light-induced circadian phase resetting and fear conditioning behaviors. Together this suggests during evolution, similar processes underlying metaplasticity in more simple circuits may have been redeployed in higher-order brain regions. Therefore, this notion predicts a model that LTP and metaplasticity may exist in neural circuits of other species, through phylogenetically conserved pathways, leading to several testable hypotheses.
"Finally, might editing of voltage-activated K + channels play a role? Against this position, only K V 1.1 channels are known to be RNA edited (Bhalla et al., 2004), while SCN neurons have been reported to express K V 3.1 (Espinosa et al., 2008; Itri et al., 2005), K V 3.2 (Itri et al., 2005), K V 4.1 and K V 4.2 (Itri et al., 2010). In fact, K V 1.1 knockout mice exhibit intact circadian rhythms, so long as overt seizure activity is controlled (Fenoglio- Simeone et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Adenosine-to-inosine RNA editing is crucial for generating molecular diversity, and serves to regulate protein function through recoding of genomic information. Here, we discover editing within Ca(v)1.3 Ca²⁺ channels, renown for low-voltage Ca²⁺-influx and neuronal pacemaking. Significantly, editing occurs within the channel's IQ domain, a calmodulin-binding site mediating inhibitory Ca²⁺-feedback (CDI) on channels. The editing turns out to require RNA adenosine deaminase ADAR2, whose variable activity could underlie a spatially diverse pattern of Ca(v)1.3 editing seen across the brain. Edited Ca(v)1.3 protein is detected both in brain tissue and within the surface membrane of primary neurons. Functionally, edited Ca(v)1.3 channels exhibit strong reduction of CDI; in particular, neurons within the suprachiasmatic nucleus show diminished CDI, with higher frequencies of repetitive action-potential and calcium-spike activity, in wild-type versus ADAR2 knockout mice. Our study reveals a mechanism for fine-tuning Ca(v)1.3 channel properties in CNS, which likely impacts a broad spectrum of neurobiological functions.
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