Graphical Abstract Highlights d Study of behavior and EEG in three partially trisomic mouse models of Down syndrome (DS) d These mutant mice show non-overlapping differences in spatial working memory function d Behavioral changes segregate with distinct EEG abnormalities in the hippocampus and mPFC d This links cognitive deficits to specific changes in hippocampal and mPFC circuit dynamics SUMMARYAltered neural dynamics in the medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder Down syndrome (DS). Here, we demonstrate non-overlapping behavioral differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial working memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, and Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice show slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, and increased modulation of hippocampal high gamma); Dp10Yey mice show impaired alternation performance and reduced theta modulation of hippocampal low gamma; and Dp17Yey mice are not significantly different from the wild type. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.

No abstract

24 7 These authors contributed equally 25 8 Correspondence: m.walker@ucl.ac.uk 26 27 41 42

No abstract