Hippocampal circuit-specific enhancement of GABA-inhibition caused by discrete gene regions in a Down syndrome model

Abstract

Although Down syndrome (DS), trisomy 21, affects [~]6 million people worldwide, the neural circuit mechanisms underlying the neurophenotypes of impaired learning, memory and language are unknown. A prominent candidate mechanism involves dysfunctional GABA-signalling and GABAA receptor ligands have been proposed as therapeutics to reverse the neurophenotypic effects of DS. By investigating GABA neurotransmission in brain regions important for cognition in mouse DS models, we reveal that excessive inhibition is not a ubiquitous feature of DS but instead is brain circuit-specific demonstrating increased phasic and tonic inhibition in the dentate gyrus with no comparative changes to inhibition in CA1 and medial prefrontal cortex. In the dentate, elevated extrasynaptic GABA signalling, and interneuron numbers, likely underpin spike firing defects. We show that increased GABA inhibition is caused by increased dosage of Olig1, Olig2 and Dyrk1a. Overall, DS mice are characterised by circuit-specific dysfunctional inhibition predicted to affect cognition via sparse coding in the hippocampus.