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%% http://bibdesk.sourceforge.net/ %% Created for Walton Jones at 2015-07-27 16:11:45 17:16:12 +0900 %% Saved with string encoding Unicode (UTF-8) @article{crunelli:2006aa, Author = {Crunelli, V and Cope, D and Hughes, S}, Date-Added = {2015-07-27 08:15:39 +0000}, Date-Modified = {2015-07-27 08:16:12 +0000}, Doi = {10.1016/j.ceca.2006.04.022}, Journal = {Cell Calcium}, Month = {aug}, Number = {2}, Pages = {175--190}, Publisher = {Elsevier {BV}}, Title = {Thalamic T-type Ca2+ channels and {NREM} sleep}, Volume = {40}, Year = 2006, Bdsk-File-1 = {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}, Bdsk-Url-1 = {http://dx.doi.org/10.1016/j.ceca.2006.04.022}} @article{anderson:2005aa, Author = {Anderson, M. P. and Mochizuki, T. and Xie, J. and Fischler, W. and Manger, J. P. and Talley, E. M. and Scammell, T. E. and Tonegawa, S.}, Date-Added = {2015-07-27 07:09:04 +0000},

These include sensory neuropils (i.e., the optic and antennal lobes, the antennal mechanosensory and motor centers, the anterior ventrolateral protocerebrum, and the subesophageal zone), motor-associated neuropils (i.e., the central complex), and those associated with learning, memory, and reward (i.e., the mushroom bodies). It is still unclear, however, whether the different isoforms predicted to originate from the \emph{DmCa\textsubscript{v}3} locus will have different biophysical properties or different distributions around the brain. Sleep has emerged as a major focal point in the search for a physiological function for the T-type channels, especially in mammals. Mammalian T-type Ca\textsuperscript{2+} channels may act as sleep stabilizers and may help generate the burst firing necessary for the sleep oscillations of deep NREM sleep. Unfortunately, the three separate mammalian T-type genes all undergo alternative splicing to produce various channel isoforms that each have various biophysical properties, neuroanatomical and subcellular localizations, and varying abilities to interact with other ion channels. All these variables combine to make it difficult if not impossible to define a precise physiological role for T-type channels in sleep. Although Ca\textsubscript{v}3.1 knockout mice lack the slow wave oscillations characteristic of deep sleep and show reduced total sleep\cite{Lee:2004ey}, when the knockout is limited to the rostral midline thalamus, sleep is still reduced, but delta waves are mildly increased\cite{anderson:2005aa}. Another more recent study showed that treatment with the T-type-specific channel blocker TTA-A2 decreases wakefulness and increases delta sleep in wild type but not Ca\textsubscript{v}3.1/Ca\textsubscript{v}3.3 double knockout mice\cite{kraus:2010aa}. Therelatively subtle and sometimes confusing phenotypes of the homozygous viable Ca\textsubscript{v}3 mutant mice are often ascribed to functional compensation among the various Ca\textsubscript{v}3.1-3 isoforms. \textcolor{red}{Maybe a citation here?} It is perhaps surprising, then, that despite its broad and relatively strong expression across adult fly brains, null mutants of the one and only fly T-type channel, DmCa\textsubscript{v}3, are also homozygous viable and lack any overt phenotypes. One previous study suggested that DmCa\textsubscript{v}2, a member of the high voltage-activated (HVA) Ca\textsubscript{v}2 subfamily of Ca\textsuperscript{2+} channels, may also somehow participate in the generation of low voltage-activated (LVA) Ca\textsuperscript{2+} currents\cite{Ryglewski:2012jk}. It is, therefore, plausible that other HVA channels could be compensating for the loss of DmCa\textsubscript{v}3 in the DmCa\textsubscript{v}3-null mutants. Flies lacking DmCa\textsubscript{v}3 do, however, show a clear sleep phenotype, suggesting that if such compensation is occurring, it is inadequate in the circuits that regulate sleep/wake behavior. In mammals, T-type Ca\textsuperscript{2+} channels seem to act as sleep stabilizers that help generate the burst firing necessary for the sleep oscillations of deep NREM sleep. \textcolor{red}{citation?} In response to an inhibitory hyperpolarization, neurons with high concentrations of T-type channels generate a low-threshold Ca\textsuperscript{2+} spike that alters membrane potential enough to induce a burst of Na\textsuperscript{+}-mediated action potentials. In the thalamus, excitatory thalamocortical (TC) relay neurons express Ca\textsubscript{v}3.1 while GABAergic neurons in the nucleus reticularis thalami (nRT) express Ca\textsubscript{v}3.2 and Ca\textsubscript{v}3.3. These two populations of neurons share reciprocal connections and control each other's firing patterns. During sleep, hyperpolarization of the TC neurons by the nRT neurons generates low-threshold burst spikes attributable to Ca\textsubscript{v}3.1 activation. These burst spikes then stimulate the nRT neurons to generate low-threshold burst spikes attributable to Ca\textsubscript{v}3.2/Ca\textsubscript{v}3.3 activation. Bursting in the nRT then sends another inhibitory hyperpolarization through the TC neurons, completing the oscillatory cycle. These oscillations spread through the cortex via the cortical connections of the TC neurons leading to the familiar slow wave patterns that chracterize the NREM sleep state. \textcolor{red}{Citation?} Consistent with this model, mice lacking Ca\textsubscript{v}3.1 lack slow wave oscillations and show reduced and unstable sleep\cite{Lee:2004ey}. \textcolor{red}{Is this a model? What do we call this model? Who proposed it? And the way it is written, it sounds like it is just what happens, not a hypothesis.} \textcolor{red}{Also, what about the role of the other two channels in the nRT? Do we not have any citations for that?} In addition to this sleep-promoting role in the thalamus, T-type Ca\textsuperscript{2+} channels have also been suggested to play the opposite role in stimulating wakefulness. In wake-up call hypothesis, the low-threshold burst spikes depending on activation of T-type Ca\textsuperscript{2+} channel has a strong post-synaptic impact and thereby stimulating the cortex efficiently\cite{swadlow:2001aa}, which may help the sensation or attention to specific sensory stimuli at the cortex. \textcolor{red}{Sure you want to do this? This reference is basically saying this wake-up call hypothesis is dumb. And the real reference is Sherman 1996.} Another study showed that T-type channel inhibition with specific blocker TTA-A2 decreased wake and increased delta sleep, but not in Ca\textsubscript{v}3.1/Ca\textsubscript{v}3.3 double knockout mice\cite{kraus:2010aa}. \textcolor{red}{I thought there were no specific blockers. What is TTA-A2?} These controversial and complex results suggest that the role of mammalian T-type calcium channels in sleep regulation may complex. In this study, we show that DmCa\textsubscript{v}3-null mutants sleep more than controls, suggesting an overall wake-promoting role for DmCa\textsubscript{v}3. This wake-promoting function seems to be independent of the circadian clock, as DmCa\textsubscript{v}3-null mutants show weak but significant rhythmicity in constant darkness and normal oscillation of the core clock gene \emph{period}.