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 NMDA receptor (NMDAR) currents were reduced. Furthermore, dendritic inhibition was mediated via nonlinear α5-subunit containing GABAA 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 α5-GABAA R-mediated inhibition rescued both, burst-induced synaptic NMDA receptor 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. SIGNIFICANCE STATEMENT Mild to moderate intellectual disability is a prominent feature of Down Syndrome. Previous studies in mouse models suggest that increased synaptic inhibition is a main factor for decreased synaptic plasticity, the cellular phenomenon underlying memory. The present study shows that increased inhibition specifically onto dendrites together with reduced NMDA receptor content in excitatory synapses may be the cause. Reducing a slow nonlinear component that is specific to dendritic inhibitory inputs and mediated by α5 subunit-containing GABAA receptors rescues both NMDA receptor activation and synaptic plasticity.