Early postnatal reelin treatment suppresses epileptic spasms in a rat model of cortical malformation.

Malformation of cortical development (MCD) is a major cause of intractable epilepsy and developmental delay in childhood. Reelin, an extracellular matrix glycoprotein, regulates neuronal migration and interneuron development. Therefore, we investigated the therapeutic potential of early postnatal reelin treatment in a rat model of MCD induced by prenatal methyazoxymethanol acetate (MAM) exposure at embryonic day 15. The neonatal rats received either recombinant mouse reelin (10 or 2.5 μg/kg) or vehicle once every 2 days from postnatal day (P) 2 to P14. On P15, N-methyl-D-aspartic acid (NMDA)-induced spasms were evaluated. The 2.5 μg/kg reelin group showed a significant reduction in the number of NMDA-induced spasms compared with the vehicle group (p = 0.043). Further analyses in the 2.5 μg/kg group revealed increase in the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 2 (AMPAR2) and calcium/calmodulin-stimulated protein kinase II (CaMKII), and decreased levels of postsynaptic density protein 95 (PSD95), AMPAR3, and NMDA receptor 1 (NMDAR1) (p < 0.05). Importantly, a marked increase in cortical interneuron expression was observed, suggesting enhanced inhibitory signaling as a key mechanism for the antispasmodic effect. In addition, magnetic resonance imaging showed no significant changes in cortical metabolites, and Golgi staining showed that dendritic arborization remained unchanged. Behavioral assessments revealed no adverse effects associated with reelin administration. In conclusion, early postnatal reelin treatment effectively suppressed spasm susceptibility in MCD rats, likely through increased interneuron expression and selective modulation of synaptic protein levels. These findings support further investigation of reelin as a potential therapeutic strategy for epilepsy associated with MCD.