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DYRK1A OVEREXPRESSION INCREASES NORADRENERGIC TONE AND IMPAIRS CONTEXTUAL MEMORY THROUGH LOCUS COERULEUS DYSREGULATION IN BAC-DYRK1A MICE
Juan Luis Musoles Lleóand 5 co-authors
Centre for Genomic Regualtion (CRG), The Barcelona Institute of Science and Technology (BIST)
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS07-10AM-334
Presentation
Date TBA
Board: PS07-10AM-334
Event Information
Poster Board
PS07-10AM-334
Poster
View posterAbstract
DYRK1A is a dosage-dependent kinase implicated in cognitive dysfunction in Down syndrome (DS), yet the neurochemical mechanisms linking DYRK1A overexpression to memory deficits remain unclear. In our study, we investigated the involvement of the noradrenergic signalling in the cognitive impairment driven by Dyrk1A overexpression.
We used contextual fear conditioning as a readout of hippocampal-dependent memory and interrogated the noradrenergic system status in the locus coeruleus (LC), and the hippocampus (HC), as target region involved in memory and learning in a transgenic mouse overexpressing Dyrk1A (TgBAC-Dyrk1A). In the locus coeruleus we evaluated tyrosine hydroxylase (TH) expression by Western blot and TH+ neurons using stereological quantification. Noradrenaline levels in HC were quantified using HPLC.
TgBAC-Dyrk1A mice exhibited impaired contextual fear memory, compared to wild-type mice, but preserved non-contextual fear memory. This deficit was accompanied by increased TH protein levels and TH+ neurons in the LC. This enhanced noradrenergic tone led to an increase in HC noradrenaline levels, with no changes in other catecholamines. Normalization of Dyrk1A levels specifically in the LC rescued contextual fear memory performance.
Our results evidence aberrant noradrenergic signalling as a mechanistic link between DYRK1A dosage and cognitive dysfunction, highlighting the locus coeruleus as a critical region in Dyrk1A-dependent memory deficits.
We used contextual fear conditioning as a readout of hippocampal-dependent memory and interrogated the noradrenergic system status in the locus coeruleus (LC), and the hippocampus (HC), as target region involved in memory and learning in a transgenic mouse overexpressing Dyrk1A (TgBAC-Dyrk1A). In the locus coeruleus we evaluated tyrosine hydroxylase (TH) expression by Western blot and TH+ neurons using stereological quantification. Noradrenaline levels in HC were quantified using HPLC.
TgBAC-Dyrk1A mice exhibited impaired contextual fear memory, compared to wild-type mice, but preserved non-contextual fear memory. This deficit was accompanied by increased TH protein levels and TH+ neurons in the LC. This enhanced noradrenergic tone led to an increase in HC noradrenaline levels, with no changes in other catecholamines. Normalization of Dyrk1A levels specifically in the LC rescued contextual fear memory performance.
Our results evidence aberrant noradrenergic signalling as a mechanistic link between DYRK1A dosage and cognitive dysfunction, highlighting the locus coeruleus as a critical region in Dyrk1A-dependent memory deficits.
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