Enhanced Dendritic Inhibition and Impaired NMDAR Activation in a Mouse Model of Down Syndrome

Down syndrome (DS) or Trisomy 21 is a developmental disorder leading to cognitive deficits, including disruption of hippocampus-dependent learning and memory. Enhanced inhibition has been suggested to underlie these deficits in DS based on studies using the Ts65Dn mouse model. Here we show that, in this mouse model, GABAergic synaptic inhibition onto dendrites of hippocampal pyramidal cells is increased. By contrast, somatic inhibition was not altered. In addition, synaptic NMDAR currents were reduced. Furthermore, dendritic inhibition was mediated via nonlinear alpha 5-subunit containing GABA(A)Rs that closely matched the kinetics and voltage dependence of NMDARs. Thus, enhanced dendritic inhibition and reduced NMDA currents strongly decreased burst-induced NMDAR-mediated depolarization and impaired LTP induction. Finally, selective reduction of alpha 5-GABA(A)R-mediated inhibition rescued both burst-induced synaptic NMDAR activation and synaptic plasticity. These results demonstrate that reduced synaptic NMDAR activation and synaptic plasticity in the Ts65Dn mouse model of DS can be corrected by specifically targeting nonlinear dendritic inhibition.