Infantile Spasms in Pediatric Down Syndrome: Potential Mechanisms Driving Therapeutic Considerations

Infantile spasms are common in Down Syndrome (DS), but the mechanisms by which DS predisposes to this devastating epilepsy syndrome are unclear. In general, neuronal excitability and therefore seizure predisposition results from an imbalance of excitation over inhibition in neurons and neural networks of the brain. Animal models provide clues to mechanisms and thereby provide potential therapeutic approaches. Ts65Dn mice have been the most widely used animal model of DS. In this model, there is evidence for both abnormal cerebral excitation and inhibition: infantile spasms-like clinical and electrographic activity can be elicited by the administration of gamma-aminobutyric acid (GABA)-B receptor agonist, gamma-butyrolactone (GBL), and depolarizing GABA-A responses persist beyond the age of their usual switch to hyperpolarized responses. But despite its widespread use, the Ts65Dn model may be suboptimal because of the absence of numerous genes that are triplicated in human DS and the presence of numerous genes that are not triplicated in human DS. Recently, a transchromosomic mouse artificial chromosome 21 (TcMAC21) mouse model has been developed, which carries a copy of human chromosome 21 and therefore has a genetic composition more similar to human DS. As in Ts65Dn mice, exposure of TcMAC21 mice to GBL results in epileptic spasms, and aberrant excitation has also been demonstrated. This review summarizes excitatory and inhibitory dysfunction in models of DS that may play a role in the generation of seizures and infantile spasms, providing a perspective on past studies and a prelude for future ones. Further elucidation will hopefully lead to rational therapeutic options for DS children with infantile spasms.