Altered synaptic functions in a humanized mouse model of down syndrome (TcMAC21): Implications for seizure susceptibility.

It is not understood why children with Down syndrome (DS, trisomy of chromosome 21) have an increased risk of seizures, including infantile spasms and tonic-clonic seizures. Using a novel humanized mouse model of DS (TcMAC21), we recently showed that TcMAC21 mice express an increased propensity to infantile spasms and demonstrate an increased neocortical synaptic excitation-to-inhibition ratio. To understand the pathophysiology of DS that may predispose animals to increased seizure susceptibility, we investigated 1) kainic-acid receptor (KAR)-mediated excitation, 2) gamma-aminobutyric acid receptors A and B (GABAAR and GABABR)-mediated inhibition, and 3) synaptojanin 1 (SYNJ1) function in TcMAC21 mice, as genes encoding KAR, GABABR and SYNJ1 are among those triplicated in DS. Layer V neocortical neurons were recorded using whole-cell patch-clamp recordings to test KAR, GABAAR, GABABR, and SYNJ functions. TcMAC21 neurons responded to focal KA application with significantly larger currents than control euploid neurons. GABAAR-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) were less frequent in TcMAC21 than in euploid neurons while sIPSC amplitudes remained unchanged. Bath application of a GABABR agonist, baclofen, caused similar hyperpolarization in TcMAC21 and euploid neurons. During repetitive synaptic stimulation, excitatory postsynaptic currents (EPSCs) in TcMAC21 neurons decayed slower and to a lesser extent than control euploid neurons, indicating less transmitter depletion (i.e., enhanced synaptic vesicle trafficking). These data provide the first physiological evidence for gain-of-function of KAR and SYNJ1, and altered GABA-mediated synaptic function in TcMAC21 mice, and may represent some important DS-specific mechanisms of seizure pathogenesis.