Astrocytes seen helping maintain circadian rhythms: Mouse study
Results lend support to astrocytes as potential targets in Parkinson’s
Neuron-supporting cells called astrocytes produce regular pulses of gamma-aminobutyric acid (GABA), a chemical that suppresses excessive brain activity, that appear to help maintain the body’s circadian rhythms and consistent sleep-wake cycles.
That’s according to a study in mice. The findings, if confirmed in humans, may “help us to better understand how the brain keeps time and how astrocytes work together with neurons,” Marco Brancaccio, MD, the study’s senior author and a lecturer in the Department of Brain Sciences at Imperial College London, said in a university news story.
Understanding how astrocytes act to help the brain with timekeeping “could potentially lead to new ways to treat disrupted circadian rhythms in insomnia, and even help to slow the onset of dementia,” Brancaccio said.
This could be particularly relevant for people with neurodegenerative diseases like Parkinson’s, in which astrocytes are pushed into overdrive. Sleep problems in these diseases are common and often linked to faster cognitive decline. In Parkinson’s, targeting astrocytes is seen as a potential treatment strategy to slow neurodegeneration.
The study, “Rhythmic astrocytic GABA production synchronizes neuronal circadian timekeeping in the suprachiasmatic nucleus,” was published in The EMBO Journal.
Circadian rhythms
Parkinson’s is a neurodegenerative disease marked by the progressive loss of dopaminergic neurons, or the neurons that produce a major brain chemical messenger called dopamine. This leads to motor and nonmotor symptoms, including slowed movement, tremors, abnormal involuntary bodily processes, and a disrupted sleep-wake cycle.
Research suggests that interfering with the circadian clock, the internal biological clock that regulates various physiological and behavioral processes over a 24-hour cycle, may make dopaminergic neurons more prone to damage.
Previous work by Brancaccio and colleagues showed that astrocytes, star-shaped brain cells known to provide support to neurons, can drive and sustain circadian behavior in mice.
Reactive astrocytes, or those undergoing several changes in response to damage in surrounding tissue due to neurodegenerative diseases or injury, are a hallmark of Parkinson’s and other neurodegenerative diseases. These abnormal cells are known to promote inflammation, which is thought to contribute to neurodegeneration.
In the early stages of disease, these important mechanisms of astrocytes, including those regulating circadian processes, “may be derailed, gradually weakening the core circuitry of the brain,” Brancaccio said.
However, “the nature of the temporal information generated by astrocytes is largely unknown,” the researchers wrote.
Brancaccio’s team identified a mechanism by which astrocytes seem to regulate the circadian rhythm in the brain.
Looking at mice’s suprachiasmatic nucleus, a brain region that regulates most circadian rhythms in the body, the researchers found that astrocytes produce a rhythmic pulse of another major chemical messenger, GABA, that peaked every 24 hours.
This rhythmic pulse was found to act as a “chemical metronome,” synchronizing neuronal activity in the suprachiasmatic nucleus, the university said.
“Our research highlights a surprising role for astrocytes in the brain’s internal clock system,” said Natalie Ness, the study’s first author and a PhD researcher at Brancaccio’s lab. “These cells produce a daily rhythm of GABA – a signalling molecule normally associated with neurons,” which “helps fine-tune the brain’s timekeeping across the day,” Ness said.
Blocking astrocyte-specific enzymes involved in GABA disrupted GABA rhythmic pulses in the suprachiasmatic nucleus, further pointing to astrocytes as the cells creating such pulses.
“When we block or disrupt this astrocyte-derived signal,” Ness said, there was a disruption of “activity and gene [activity] patterns known to be crucial in maintaining circadian rhythms in physiology and behaviour.” This can indirectly impact the body’s circadian rhythm and the sleep-wake cycle.
The study “provides a general blueprint for understanding how astrocytes encode temporal information underlying complex behaviors in mammals,” the researchers wrote.
“As we look for ‘tipping points’ by which disrupted sleep-wake cycles could lead us to the path of disease, bolstering astrocytic GABA rhythms appears an exciting candidate for preventative interventions,” Brancaccio said.
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