Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A

In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum. Through computational modeling, we determined that these alterations resulted in reduced storage capacity and compromised integration of inputs, with decreased high gamma oscillations. Contrary to prevailing assumptions, our model suggests that deficits in neuronal architecture, rather than over-inhibition, primarily contribute to the reduced network. We explored the potential of environmental enrichment (EE) as a therapeutic intervention and found that it normalized the excitation-inhibition balance, restored LTP, and improved short-term recognition memory. Interestingly, we observed transient significant dendritic remodeling, leading to recovered high gamma. However, these effects were not sustained after EE discontinuation. Based on our findings, we conclude that Dyrk1A overexpression-induced layer-specific neuromorphological disturbances impair the encoding of place and temporal context. These findings contribute to our understanding of the underlying mechanisms of Dyrk1A-related hippocampal deficits and highlight the challenges associated with long-term therapeutic interventions for cognitive impairments.

Automated summary

This study examined the impact of Dyrk1A overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. The findings revealed that mice overexpressing Dyrk1A exhibited impaired recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation. Computational modeling suggested that these alterations resulted in reduced storage capacity and compromised integration of inputs. Environmental enrichment was found to be a potential therapeutic intervention, restoring balance and improving memory, but the effects were not sustained after discontinuation.