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Mitchell, S. B.

Publications and source records attributed to Mitchell, S. B..

2 recordsLinked to original sources
bioRxiv2019

Calcium-induced calcium release in noradrenergic neurons of the locus coeruleus

The locus coeruleus (LC) is a nucleus within the brainstem that consists of norepinephrine-releasing neurons. It is involved in broad processes including autonomic regulation, and cognitive and emotional functions such as arousal, attention and anxiety. Understanding the mechanisms that control the excitability of LC neurons is important because they innervate widespread regions of the central nervous system. One of the key regulators is the cytosolic calcium concentration ([Ca2+]c), the increases in which can be amplified by calcium-induced calcium release (CICR) from the intracellular calcium stores. Although the electrical activities of LC neurons are regulated by changes in [Ca2+]c, the extent of CICR involvement in this regulation has remained unclear. Here we show that CICR hyperpolarizes acutely dissociated LC neurons of the rat brain and demonstrate the pathway whereby it does this. When CICR was activated by extracellular application of 10 mM caffeine, LC neurons were hyperpolarized in the current-clamp mode of the patch-clamp recording, and the majority of neurons showed an outward current in the voltage-clamp mode. This outward current was accompanied by an increase in membrane conductance, and its reversal potential was close to the K+ equilibrium potential, indicating that it is mediated by the opening of K+ channels. The outward current was generated in the absence of extracellular calcium and was blocked when the calcium stores were inhibited by applying ryanodine. Pharmacological experiments indicated that the outward current was mediated by Ca2+-activated K+ channels of the non-small conductance type. Finally, the application of caffeine led to an increase in the [Ca2+]c in these neurons, as visualized by fluorescence microscopy. These findings delineate a mechanism whereby CICR suppresses the electrical activity of LC neurons, and indicate that it could play a dynamic role in modulating the LC-mediated noradrenergic tone in the brain.

neuroscience↗
bioRxiv2019

Transcriptome profiles in brains of mice heterozygous for a DYT1 dystonia-associated mutation in the endogenous Tor1a gene

In patients with the brain disorder dystonia, body movement is severely affected - with involuntary muscle contractions and abnormal postures, causing extensive deterioration of the patients quality of life. The most common inherited form of this disorder is DYT1 dystonia, which is caused by a mutation in TOR1A gene and autosomal dominant. The molecular mechanisms that underlie the effects of the TOR1A mutation on brain function remain unclear. To understand these, we examined the gene expression profiles (transcriptome) in four brain regions (cerebral cortex, hippocampus, striatum and cerebellum) in a mouse model, the heterozygous {Delta}E-torsinA knock-in mice which genetically reproduce the mutation in DYT1 dystonia. The samples were obtained at 2 to 3 weeks of age, a period during which synaptic abnormalities have been reported. Pairwise comparisons of brain regions revealed differential gene expression irrespective of genotype. A comparison of heterozygous to wild-type mice failed to reveal genotype-dependent differences in gene expression in any of the four brain regions when examined individually. However, genotype-dependent differences became apparent when the information for all brain regions was combined. These results suggest that any changes in the transcriptome within a brain region were subtle at this developmental stage, but that statistically significant changes occur across all brain regions. Such changes in the transcriptome, although subtle in degree, could underlie the processes that give rise to DYT1 dystonia.

neuroscience↗