Badania obrazowe w czasie rzeczywistym w modelu myszy z ogniskową dysplazją kory mózgowej pokazują rozszerzanie się zmian i utratę neuronalnego zaangażowania przed wyładowaniami
Longitudinal Imaging in a Mouse Model of Focal Cortical Dysplasia Reveals Lesion Expansion and Loss of Pre-Discharge Neuronal Recruitment
W skrócie
[Preprint - wstępne wyniki] Badacze obserwowali za pomocą specjalnych technik obrazowania, jak zmienia się ogniskowa dysplazja kory mózgowej (przyczyna trudnych do leczenia napadów epilepsji) u myszy na przestrzeni czasu. Odkryli, że zmiana nie jest nieruchoma - stopniowo się rozszerza, a neurony trací zdolność do zapowiadania napadów. Wyniki sugerują, że chirurgiczne usunięcie zmienionego fragmentu kory mózgowej powinno być wykonane jak najwcześniej, gdy wciąż istnieje szansa na zatrzymanie choroby.
Oryginalny abstract (angielski)
ABSTRACT Objective: Focal cortical dysplasia type II (FCD II) is a leading cause of drug-resistant focal epilepsy, yet how its lesional circuits behave and change over time in vivo has not been directly observed. Methods: We used a mouse model of FCD II carrying the patient-derived gain-of-function mTORp.L2427P variant introduced by in utero electroporation. Through a chronic cranial window over the lesion, we performed repeated in vivo two-photon calcium imaging of identified dysmorphic neurons, pyramidal cells, and VIP interneurons at defined time points, combined with video-EEG monitoring, to determine seizure status and relate cellular activity to interictal discharges. Results: The lesion was not static in adulthood. Dysplastic cortex expanded progressively. This expansion occurred without the tenascin R/C accumulation reported in human FCD II, and was partly explained by continued somatic growth of dysmorphic neurons. Dysmorphic neurons were generally hypoactive; in seizing mice, both dysmorphic and pyramidal cell activity progressively declined, whereas VIP interneuron activity increased slightly in non-seizing animals. In non-seizing lesional cortex, neurons were reliably recruited immediately before interictal discharges. By late disease stages, pre-discharge recruitment had weakened to the point that lesional layer 2/3 neurons were no more active before discharges than expected by chance. Significance: These findings recast FCD II as a lesion that continues to remodel structurally and functionally throughout adulthood, and does so most markedly in animals with seizures. Growth, a cell-type-specific shift in spontaneous activity, and a progressive loss of the lesion's temporal lead over interictal discharges together suggest that FCD II is a dynamically evolving lesion whose relationship to epileptiform activity changes over time. If the lesion progressively loses its generative role, the window in which removing it can arrest the disease is finite, consistent with clinical evidence favoring earlier surgery.