LONGITUDINAL <EM>IN VIVO</EM> TWO-PHOTON IMAGING OF CORTICAL OLIGODENDROCYTE DIFFERENTIATION DYNAMICS IN A MOUSE MODEL OF FOCAL CORTICAL DYSPLASIA TYPE II

Myelination is increasingly recognized as a dynamic process adapting to neuronal network activity. Focal cortical dysplasia type II (FCDII) is a malformation of cortical development associated with pharmacoresistant epilepsy. It arises from somatic mutations causing mTOR pathway hyperactivation in excitatory neurons, leading to network remodelling and seizures. How myelination evolves with seizure burden over disease progression remains poorly understood.
To address this question, we performed longitudinal in vivo two-photon imaging in transgenic mice in which newly differentiated oligodendrocytes were fluorescently labelled, allowing us to track differentiation dynamics of cortical oligodendrocytes in a mouse model of FCDII. FCDII was induced by in utero electroporation of a plasmid carrying a mutated mTOR gene, causing hyperactivation of the mTOR pathway in excitatory neurons of cortical layers 2/3. To distinguish the effects of seizures from mTOR hyperactivity, we used an additional cohort in which seizures were evoked by electrical stimulation.
Our preliminary data show that in animals with FCDII, the proportions of stable and newly generated myelinating oligodendrocytes were comparable to those in control animals. However, both FCDII and control animals displayed a reduced pool of immature oligodendrocytes compared to animals in which seizures were electrically induced. In the electrically stimulated animals, we observed increased dynamics within the immature oligodendrocyte pool but a reduced number of stable myelinating oligodendrocytes.
These findings suggest that electrically induced seizures appear to stimulate differentiation of the immature oligodendrocytes, although full maturation into myelinating oligodendrocytes is compromised. In contrast, in animals with FCDII, neuronal activity-dependent myelination may be disrupted.