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

Abstract

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 ¿ 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 ¿. 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.

We acknowledge support of the Spanish Ministry of Economy and Competitiveness (MINECO), “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208. The research leading to these results has received funding from MINECO (SAF2013-49129-C2-1-R; PID2022-141900OB-I00 and PID2019-110755RB-I00/AEI/10.13039/501100011033), H2020 SC1 Gene overdosage and comorbidities during the early lifetime in DS GO-DS21-848077, Jerôme Lejeune Foundation #2002, the NIH grant R01 EB028159 We acknowledge support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa ((CEX2020-001049-S, MCIN/AEI/10.13039/501100011033)) and the CERCA Programme/Generalitat de Catalunya. The CIBER of Rare Diseases is an initiative of the ISCIII.

Peer Reviewed

Postprint (published version)