Biology subjects

Goble, T.

Publications and source records attributed to Goble, T..

2 recordsLinked to original sources

bioRxiv2025

A meningeal circadian clock and brain state co-ordinately enhance macromolecular clearance during wake

The removal of brain waste is thought to be regulated by the circadian clock and sleep-wake cycle. A meningeal scavenger cell population, called mural Lymphatic Endothelial Cells (muLECs), uptake macromolecules from the cerebrospinal fluid (CSF) and are poised to clear soluble brain waste. Whether CSF clearance is regulated across the 24-hour day is unknown. Using a quantitative, in vivo assay in zebrafish, we show that the capacity of muLECs to remove macromolecules is highest during the waking day. The muLEC protein uptake is regulated by a cell-autonomous circadian oscillator that drives rhythmic protein levels of Mannose Receptor 1a (Mrc1a); in contrast, lipoprotein uptake increases as a function of time spent awake. Thus, circadian and brain state cues independently maximize muLECs function during wake. Consistently, muLECs are required for normal recovery after the heightened metabolic demand of a seizure, suggesting that muLEC clearance contributes to both normal and disrupted brain homeostasis. Impact StatementA meningeal scavenger cell population called Mural Lymphatic Endothelial Cells preferentially clear macromolecules from the CSF during the waking day, and this uptake is regulated independently by brain state and circadian cues in a substrate-specific manner.

neuroscience↗

bioRxiv2023

BK channel gain-of-function disrupts limb control by suppressing neurotransmission during a critical developmental window

Gain-of-function mutations in BK potassium channels (BK GOF) cause debilitating involuntary limb movements. BK channels modulate action potential shape and neurotransmission in mature neurons, yet some BK GOF mutations also cause neurodevelopmental morbidities. Thus, whether BK GOF impairs limb control by altering the excitation/inhibition of mature motor circuits, or by disrupting their development, remains unclear. To address this issue, we developed a genetic method enabling spatiotemporal control of BK channel expression in neurons of the fruit fly, Drosophila. In concert with high-resolution measurements of limb kinematics, we demonstrate that GOF BK channels act during a narrow neurodevelopmental period to perturb limb control in adult flies. During this period, BK GOF alters synaptic localisation of the key active zone protein Bruchpilot and suppresses excitatory neurotransmission. In a wild-type background, we find that reducing neural activity during neurodevelopment yields similar motor defects to those observed in BK GOF flies. Conversely, enhancing neural excitability during development rescues alterations in limb kinematics in BK GOF flies. Collectively, our results suggest that BK GOF perturbs limb control largely by disrupting activity-dependent aspects of neuronal development.

neuroscience↗