Restoring the gene landscape in CDD

The hind-limb clasping test is one of the most widely used motor assays in mouse models of neurological disease. A mouse is lifted by the tail, and an observer scores whether it pulls its hind legs in toward its body. It's simple, but it depends on human judgement, varies between raters, and reduces movement to a coarse category. We built VECTR-Clasp to make the assay objective and to get far more out of it.

Neuroscientists have long faced a trade-off. Measuring the nucleus meant slicing tissue thin, which cuts the dendrites, while chemical clearing keeps dendrites whole but warps the cell body. We got around that by imaging Golgi-Cox-stained mouse brain with 3D X-ray microscopy. The stain fills the cytoplasm but consistently leaves the nucleus unstained, and under X-ray that gap shows up as a sharply defined dark void inside the bright cell body. Instead of treating this as a flaw, we use it as a built-in nuclear channel, with no extra labels, sectioning, or clearing needed.

Our hypothesis is that microRNAs are dysregulated in CDKL5 Deficiency Disorder and that correcting them with antisense oligonucleotides (ASOs) could rescue observed deficits. The project builds on the group's discoveries that miR-134 inhibition reduces hyperexcitability in drug-resistant epilepsy and that miR-335-5p controls voltage-gated sodium channels. Candidate ASOs are delivered in vivo and evaluated using chronic video-EEG, behavioural testing and slice electrophysiology.

This project examines the morphology of neurons in Cdkl5-deficient mice and links structural changes to the molecular pathways disrupted by CDKL5 loss.