Quasimodo Illuminates the Secret to the Ticking of Our Internal Clocks

Summary: Researchers have identified three novel proteins that act together on the surface of clock neurons to make the clock light responsive.

Source: University of Bristol.

Drosophila fruit flies are so named after the Latin for “dew loving” because they are more active at dawn and dusk. This strong sense of circadian rhythm (the 24 hour time cycle) is generated by a clock that ticks in the brain of all animals including humans.

The fly’s clock consists of about one hundred neurons in its 100,000-neuron brain, which can fit on a pin head. Inside each clock neuron is a “molecular clock” that consists of clock genes, which switch each other on and off every night and day.

Writing in the journal PNAS today, a team of researchers, led by Dr Edgar Buhl and Dr James Hodge from the University of Bristol in collaboration with Professor Ralf Stanewsky’s group at UCL, explain how they identified three novel proteins that act together on the surface of clock neurons to make the clock light responsive.

“To be useful for an organism, circadian clocks need to be synchronized (or reset) to the natural environment cycles of light and temperature, much like you need to reset your alarm clock or watch when you change time zone,” said Dr Hodge from Bristol’s School of Physiology, Pharmacology and Neuroscience.

The findings could ultimately have implications for identifying novel membrane drug targets for sleeping disorders and jetlag, while furthering scientific understanding of the relationship between body clocks and health, as well as ageing and neurodegenerative disease.

The research builds on one of Professor Stanewsky’s earlier discoveries regarding the Quasimodo gene, named after the fact that some mutant versions of the gene caused Drosophila to have hunched backs.

Using a red fluorescent protein to illuminate the clock neurons and record electrical activity in the brain, the authors showed that Quasimodo regulates light responses in the fly’s clock neurons, thereby controlling the circadian rhythm.

Image shows a brain.

Cartoon of the front of the Drosophila brain showing the ~100 clock neurons. The current study recorded from the 4 large pigment dispersing factor (PDF)-expressing ventral lateral neurons (LNv) clock neurons that receive several light inputs. B, The whole brain preparation used in the study showing the PDF::Red Fluorescent Protein labelled clock neurons for recording (the band in the middle is a nylon thread holding the brain down in the recording chamber) and C, detail of a clock neuron with recording electrode (from below and middle). NeuroscienceNews.com image is credited to the researchers.

Recordings from the fly clock neurons were taken at different times of the day, showing that they were more excitable in the day as opposed to at night. Using fly genetics to alter the amount of Quasimodo in the clock neurons, the researchers found that increasing Quasimodo caused the clock neurons to be less active as they would be at night, while decreasing Quasimodo had the opposite effect.

The Quasimodo protein is localised at the cell surface and electrical activity is generated in the membrane by small pores called ion channels. Therefore attention was turned to ion channels that were known to be active in clock neurons and that could potentially interact with Quasimodo to form a “membrane clock”, which could control these day-night differences in electrical activity.

The first component of the membrane clock was a potassium channel called Shaw (dKv3.1), which Dr Hodge and Professor Stanewsky had previously shown to be important for circadian rhythms. The second component was the ion transporter NKCC, which also plays an important role in the day/activity changes in the mammalian brain clock. This latest study shows that Quasimodo interacts with Shaw and NKCC to form a membrane clock that controls daily changes in electrical activity of clock neurons, which allows the clock to respond to light.

About this neuroscience research article

Source: Aliya Mughal – University of Bristol
Image Source: NeuroscienceNews.com image is credited to the researchers.
Original Research: Abstract for “Quasimodo mediates daily and acute light effects on Drosophila clock neuron excitability” by Edgar Buhl, Adam Bradlaugh, Maite Ogueta, Ko-Fan Chen, Ralf Stanewsky, and James J. L. Hodge in PNAS. Published online November 7 2016 doi:10.1073/pnas.1606547113

Cite This NeuroscienceNews.com Article
University of Bristol “Quasimodo Illuminates the Secret to the Ticking of Our Internal Clocks.” NeuroscienceNews. NeuroscienceNews, 7 November 2016.
<http://neurosciencenews.com/quasimodo-circadian-clock-5453/>.
University of Bristol (2016, November 7). Quasimodo Illuminates the Secret to the Ticking of Our Internal Clocks. NeuroscienceNew. Retrieved November 7, 2016 from http://neurosciencenews.com/quasimodo-circadian-clock-5453/
University of Bristol “Quasimodo Illuminates the Secret to the Ticking of Our Internal Clocks.” http://neurosciencenews.com/quasimodo-circadian-clock-5453/ (accessed November 7, 2016).

Abstract

Quasimodo mediates daily and acute light effects on Drosophila clock neuron excitability

We have characterized a light-input pathway regulating Drosophila clock neuron excitability. The molecular clock drives rhythmic electrical excitability of clock neurons, and we show that the recently discovered light-input factor Quasimodo (Qsm) regulates this variation, presumably via an Na+, K+, Cl− cotransporter (NKCC) and the Shaw K+ channel (dKV3.1). Because of light-dependent degradation of the clock protein Timeless (Tim), constant illumination (LL) leads to a breakdown of molecular and behavioral rhythms. Both overexpression (OX) and knockdown (RNAi) of qsm, NKCC, or Shaw led to robust LL rhythmicity. Whole-cell recordings of the large ventral lateral neurons (l-LNv) showed that altering Qsm levels reduced the daily variation in neuronal activity: qsmOX led to a constitutive less active, night-like state, and qsmRNAi led to a more active, day-like state. Qsm also affected daily changes in K+ currents and the GABA reversal potential, suggesting a role in modifying membrane currents and GABA responses in a daily fashion, potentially modulating light arousal and input to the clock. When directly challenged with blue light, wild-type l-LNvs responded with increased firing at night and no net response during the day, whereas altering Qsm, NKKC, or Shaw levels abolished these day/night differences. Finally, coexpression of ShawOX and NKCCRNAi in a qsm mutant background restored LL-induced behavioral arrhythmicity and wild-type neuronal activity patterns, suggesting that the three genes operate in the same pathway. We propose that Qsm affects both daily and acute light effects in l-LNvs probably acting on Shaw and NKCC.

“Quasimodo mediates daily and acute light effects on Drosophila clock neuron excitability” by Edgar Buhl, Adam Bradlaugh, Maite Ogueta, Ko-Fan Chen, Ralf Stanewsky, and James J. L. Hodge in PNAS. Published online November 7 2016 doi:10.1073/pnas.1606547113

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