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Published on: January 29, 2018
Imaging brain development in a KCNQ2-developmental and epileptic encephalopathy mouse model: identifying early
Charissa Millevert1, Nicholas Vidas-Guscic2, Mohit H Adhikari2
1VIB Center for Molecular Neurology, VIB, 2610, Antwerp, Belgium; Dept. of Neurology, University Hospital, 2610, Antwerp, Belgium; μNEURO Research Centre of Excellence, University of Antwerp, 2610, Antwerp, Belgium.
Background:
KCNQ2-developmental and epileptic encephalopathy (KCNQ2-DEE) is a severe neurodevelopmental disorder (NDD) characterised by early-life seizures but persistent cognitive impairment. The absence of early, quantifiable preclinical biomarkers for neurodevelopmental dysfunction limits the evaluation of new treatments. We hypothesise that key brain maturation processes are altered early in disease development and could serve as biomarkers for neurodevelopmental dysfunction.
Methods:
We performed longitudinal in-vivo brain imaging in 37 kcnq2Thr274Met/+ (KI) mice and 31 wild-type (WT) controls at three developmental stages: infancy (P14-21), juvenile (P32-42), and adulthood (P83-106). Resting-state functional MRI (rs-fMRI) assessed functional connectivity (FC), [18F]SynVesT-1 PET measured synaptic density, and diffusion tensor imaging (DTI) evaluated white and grey matter microstructure. Linear mixed models with Bonferroni correction were used to analyse genotype-by-age interactions across brain regions.
Findings:
At infant age, KI mice showed increased FC relative to WT, particularly within the default mode-like network (DMLN). During the juvenile stage, KI mice exhibited modest elevated synaptic density across brain regions, most notably in the cerebellum. By adulthood, KI mice displayed reduced FC, especially within the DMLN, compared to WT. No significant microstructural genotype-by-age interactions were found.
Interpretation:
KCNQ2-DEE disrupts neurodevelopment, with early hyperconnectivity and delayed synaptic pruning transitioning to adult hypoconnectivity. While this pattern is too subtle to use as a standalone biomarker, these findings establish a foundation for their use in longitudinal preclinical research targeting early therapeutic intervention.
Funding:
Supported by the University of Antwerp, Fonds Wetenschappelijk Onderzoek, the Queen Elisabeth Medical Foundation, the European Joint Programme on Rare Disease, and Fondation Lejeune.
