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Seminar

Synapse-specific contributions to altered E-I balance in a Mouse Model of Down Syndrome

Dr Jan Michael SCHULZ
Department of Biomedicine, University of Basel, Switzerland

Friday, December 6th 2019 - 11 a.m. - Meeting room 3013, ICS
Hosted by Yann HERAULT

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. However, a recent study has suggested that GABA may be excitatory in the Ts65Dn mouse model of Down Syndrome. We addressed this controversial issue in CA1 pyramidal neurons in hippocampal brain slices from Ts65Dn and wildtype (wt) mice. Using cell-attached and perforated-patch recordings, we found that GABA is inhibitory in Ts65Dn mice, but that the GABA reversal potential is significantly depolarized. Synaptic inhibition specifically onto dendrites was increased, whereas monosynaptic perisomatic inhibition was not changed in Ts65Dn mice. In addition, we found a ~25% reduction of NMDA receptor-mediated postsynaptic current (PSCs) relative to AMPA receptor-PSCs specifically in synapses on the apical dendrite in Ts65Dn mice. Reduction of dendritic inhibition by pharmacological modulation of α5 subunit-containing GABAA receptors enhanced NMDAR activation and rescued synaptic plasticity. Thus, the combination of increased synaptic inhibition onto dendrites and reduced NMDA receptor content may be one important contributor to impaired learning in Down Syndrome.

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