Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A
Manubens-Gil, Linus (Southeast University (SEU))
Pons-Espinal, Meritxell (Universitat de Barcelona. Institut de Biomedicina)
Gener, Thomas (Institut Català de Nanociència i Nanotecnologia)
Ballesteros-Yañez, Inmaculada (Universidad de Castilla-La Mancha)
Martínez de Lagrán, María (Center for Genomic Regulation)
Dierssen, Mara (Centro de Investigación Biomédica en Red de Enfermedades Raras)

Data:	2024
Resum:	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 γ 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 γ. 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.
Ajuts:	Ministerio de Economía y Competitividad SEV-2012-0208 Ministerio de Economía y Competitividad SAF2013-49129-C2-1-R Agencia Estatal de Investigación PID2022-141900OB-I00 Agencia Estatal de Investigación PID2019-110755RB-I00 European Commission 848077 Ministerio de Ciencia e Innovación CEX2020-001049-S
Nota:	Altres ajuts: CERCA Programme/Generalitat de Catalunya ; The CIBER of Rare Diseases is an initiative of the ISCIII
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	CA1 ; Dendritic morphology ; Down syndrome ; Environmental enrichment ; Gamma oscillations
Publicat a:	Cerebral cortex (New York, N.Y.), Vol. 34, Issue 1, (January 2024) , art. bhad431, ISSN 1460-2199

DOI: 10.1093/cercor/bhad431
PMID: 37997361

19 p, 4.3 MB

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