Increased seizure susceptibility and neocortical excitability in TcMAC21 Down syndrome mice

Seizures are a common comorbidity in children with Down syndrome (DS) yet seizure genesis in the DS brain is poorly understood. The two most common types of seizures in DS patients are infantile spasms (IS) and generalized tonic-clonic seizures. Using a novel humanized DS model (TcMAC21), we revealed an increased propensity to IS associated with a heightened neocortical excitation-inhibition ratio. Here, we examined the susceptibility of TcMAC21 mice to flurothyl-induced tonic-clonic type seizures and their propensity to epileptiform activity in neocortical-hippocampal slices. At postnatal day (P) 9-11, TcMAC21 mice exhibited significantly shorter latencies to flurothyl seizures but similar seizure durations compared with euploid controls. At P17-18, TcMAC21 mice showed both shorter seizure latencies and longer seizure durations than euploid mice. In neocortical-hippocampal slices, the frequency and duration of spontaneous epileptiform bursts (induced by 0 Mg²⁺ and 4-aminopyridine) in hippocampal CA3 and neocortical layers II/III and V were not significantly different between the euploid and TcMAC21 mice. In addition, we assessed evoked responses in layer II/III by electrical stimulation at the junction of layer VI and white matter, in the presence of a GABA_A receptor blocker, gabazine (1 uM). At P9-P13, evoked responses in layer II/III were similar between TcMAC21 and euploid mice; however, at P17-P20, the responses were significantly greater in TcMAC21 than euploid controls. Together, these data show that TcMAC21 mice exhibit heightened susceptibility to tonic-clonic seizures and an age-dependent increased neocortical excitability compared to euploid mice. These results provide new insights into the pathophysiology of seizures in DS.