Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome

Altafaj, Xavier; Martı́n, Eduardo D.; Ortiz-Abalia, Jon; Valderrama, Aitana; Lao-Peregrin, Cristina; Dierssen, Mara; Fillat, Cristina

doi:10.1016/j.nbd.2012.11.017

Cited by 66 publications

(61 citation statements)

References 35 publications

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“…In this study, normalization of the Dyrk1A copy number in the TS mouse completely rescued hippocampal LTP, indicating that the extra copy of Dyrk1A in this mouse plays a role in the alteration in synaptic plasticity. Consistent with our results, pharmacological or genetic inhibition via administration of EGCG or injection of AAV2/1-shDyrk1A, respectively, enhances hippocampal LTP in TS mice [7], [62].…”

Section: Discussionsupporting

confidence: 91%

“…A recent study [7] revealed that normalization of the Dyrk1A expression level exclusively in the hippocampus by injecting a viral vector containing inhibitory Dyrk1A shRNA (AAV2/1-shDyrk1A) did not improve the learning abilities of TS mice; however, this intervention enhanced their search strategy during the MWM test. The discrepancy between these results and the partial rescue of the performance on the MWM test found in the present study may be explained by the tissues in which Dyrk1A expression was normalized in each study.…”

Section: Discussionmentioning

confidence: 99%

“…One of these genes is dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A ( DYRK1A ), which encodes a protein kinase that performs crucial functions in the regulation of cell proliferation and multiple signaling pathways [4], [5] that contribute to normal brain development and adult brain physiology [4], [6]. Therefore, the DYRK1A gene likely plays an important role in the cognitive deficits found in DS [4], [5], [7].…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

et al. 2014

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Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/−) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

et al. 2014

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“…Our results confirm that Ts65Dn mice exhibit spatial learning deficits, but the high levels of thigmotaxis we have measured modify our current understanding of the character of these spatial memory deficits. While several studies employing the MWM paradigm never assessed thigmotaxic behavior, other studies considered thigmotaxis as a non-spatial strategy to find the platform (Shichiri et al, 2011; Altafaj et al, 2013; Garcia-Cerro et al, 2014; Souchet et al, 2014; Zhang et al, 2014). We believe that thigmotaxis behavior reflects sensorimotor and/or emotional issues that are separate from spatial L/M deficits, as discussed previously (Holmes et al, 2002; Stasko and Costa, 2004; Inostroza et al, 2011; Vorhees and Williams, 2014).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

Olmos-Serrano

Tyler

Cabral

et al. 2016

Experimental Neurology

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Mouse models have provided insights into adult changes in learning and memory in Down syndrome, but an in-depth assessment of how these abnormalities develop over time has never been conducted. To address this shortcoming, we conducted a longitudinal behavioral study from birth until late adulthood in the Ts65Dn mouse model to measure the emergence and continuity of learning and memory deficits in individuals with a broad array of tests. Our results demonstrate for the first time that the pace at which neonatal and perinatal milestones are acquired is correlated with later cognitive performance as an adult. In addition, we find that lifelong behavioral indexing stratifies mice within each genotype. Our expanded assessment reveals that diminished cognitive flexibility, as measured by reversal learning, is the most robust learning and memory impairment in both young and old Ts65Dn mice. Moreover, we find that reversal learning degrades with age and is therefore a useful biomarker for studying age-related decline in cognitive ability. Altogether, our results indicate that preclinical studies aiming to restore cognitive function in Ts65Dn should target both neonatal milestones and reversal learning in adulthood. Here we provide the quantitative framework for this type of approach.

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“…As a member of the dual-specificity tyrosine phosphorylationregulated kinase family, DYRK1A phosphorylates numerous proteins, including transcription factors, controls cell proliferation, participates in brain development (Becker, 2011;Guedj et al, 2012), and regulates Ͼ200 genes (Lepagnol-Bestel et al, 2009) and multiple signaling pathways (Guedj et al, 2012). Because of its pleiotropic functions in brain development, Dyrk1a is a strong candidate gene for the learning and neuronal abnormalities associated with DS (Becker, 2011;Guedj et al, 2012;Altafaj et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Prefrontal Deficits in a Murine Model Overexpressing the Down Syndrome Candidate GeneDyrk1a

et al. 2014

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The gene Dyrk1a is the mammalian ortholog of Drosophila minibrain. Dyrk1a localizes in the Down syndrome (DS) critical region of chromosome 21q22.2 and is a major candidate for the behavioral and neuronal abnormalities associated with DS. PFC malfunctions are a common denominator in several neuropsychiatric diseases, including DS, but the contribution of DYRK1A in PFC dysfunctions, in particular the synaptic basis for impairments of executive functions reported in DS patients, remains obscure. We quantified synaptic plasticity, biochemical synaptic markers, and dendritic morphology of deep layer pyramidal PFC neurons in adult mBACtgDyrk1a transgenic mice that overexpress Dyrk1a under the control of its own regulatory sequences. We found that overexpression of Dyrk1a largely increased the number of spines on oblique dendrites of pyramidal neurons, as evidenced by augmented spine density, higher PSD95 protein levels, and larger miniature EPSCs. The dendritic alterations were associated with anomalous NMDAR-mediated longterm potentiation and accompanied by a marked reduction in the pCaMKII/CaMKII ratio in mBACtgDyrk1a mice. Retrograde endocannabinoid-mediated long-term depression (eCB-LTD) was ablated in mBACtgDyrk1a mice. Administration of green tea extracts containing epigallocatechin 3-gallate, a potent DYRK1A inhibitor, to adult mBACtgDyrk1a mice normalized long-term potentiation and spine anomalies but not eCB-LTD. However, inhibition of the eCB deactivating enzyme monoacylglycerol lipase normalized eCB-LTD in mBACtgDyrk1a mice. These data shed light on previously undisclosed participation of DYRK1A in adult PFC dendritic structures and synaptic plasticity. Furthermore, they suggest its involvement in DS-related endophenotypes and identify new potential therapeutic strategies.

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Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome

Cited by 66 publications

References 35 publications

Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

Prefrontal Deficits in a Murine Model Overexpressing the Down Syndrome Candidate GeneDyrk1a

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