Characterization of nodular neuronal heterotopia in children

Neuronal heterotopia are seen in various pathologies and are associated wit h intractable epilepsy. We examined brain tissue from four children with su bcortical or periventricular nodular heterotopia of different aetiologies: one with severe epilepsy following focal brain trauma at 17 weeks gestation , one with hemimegalencephaly and intractable epilepsy, one with focal cort ical dysplasia and intractable epilepsy, and one dysmorphic term infant wit h associated hydrocephalus and polymicrogyria. The connectivity of nodules was investigated using histological and carbocyanine dye (DiI) tracing tech niques. DiI crystal placement adjacent to heterotopic nodules revealed nume rous DiI-labelled fibres within a 2-3 mm radius of the crystals. Although w e observed labelled fibres closely surrounding nodules, the majority did no t penetrate them. Placement of DiI crystals within nodules also identified a limited number of projections out of the nodules and in one case there wa s evidence for connectivity between adjacent nodules. The cellular and neur ochemical composition of nodules was also examined using immunohistochemist ry for calretinin and neuropeptide Y (NPY), which are normally expressed in GABAergic cortical interneurons. Within heterotopic nodules from all cases , numerous calretinin-positive neurons were identified, along with a few ce ll bodies and many processes positive for NPY. Calretinin-positive neurons within nodules were less morphologically complex than those in the cortex, which may reflect incomplete differentiation into an inhibitory neuronal ph enotype. There were also abnormal clusters of calretinin-positive cells in the overlying cortical plate, indicating that the migratory defect which pr oduces heterotopic nodules also affects development of the cortex itself. T hus, heterotopic nodules consisting of multiple neuronal cell types are ass ociated with malformation in the overlying cortical plate, and have limited connectivity with other brain regions. This abnormal development of connec tivity may affect neuronal maturation and consequently the balance of excit ation and inhibition in neuronal circuits, leading to their epileptogenic p otential.