Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage

Souchet, Benoît; Guedj, Fayçal; Sahún, Ignasi; Duchon, Arnaud; Daubigney, Fabrice; Badel, Anne; Yanagawa, Yuchio; Barallobre, Marı́a José; Dierssen, Mara; Yu, Eugene; Hérault, Yann; Arbonés, Mariona; Janel, Nathalie; Créau, Nicole; Delabar, Jean Maurice

doi:10.1016/j.nbd.2014.04.016

Cited by 108 publications

(103 citation statements)

References 62 publications

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“…Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage. 43 A recent study shows that a DYRK1A inhibitor rescues the cognitive deficit in DS mouse models and in humans. 44 A similar approach enhancing DYRK1A expression may benefit individuals with this new syndrome.…”

Section: Discussionmentioning

confidence: 99%

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from − 2 SD to − 5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broadbased gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

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Section: Discussionmentioning

confidence: 99%

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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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 pointed out, DYRK1A overexpression was found in mouse model of DS [79]. Influencing synaptic excitation/inhibition balance, DYRK1A induced excessive synaptic inhibition in the transgenic mice with DS [80]. Speculatively, since increased synaptic excitability was documented in psychiatric disorders as schizophrenia, the synaptic inhibition found in mouse model of DS may represent a possible resilience factor against the development of Psychotic symptoms in DS [81].…”

Section: Discussionmentioning

confidence: 92%

Detecting Psychiatric Profile in Genetic Syndromes: A Comparison of Down Syndrome and Williams Syndrome

Vicari¹,

Costanzo²,

Arm³

et al. 2016

J Genet Syndr Gene Ther

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The occurrence and co-occurrence of psychiatric disorders have been more frequently reported in people with Intellectual Disability (ID) than in the general population. The present study was aimed at verifying whether the psychiatric profile of individuals with ID is just a consequence of ID or derives from a specific genotype. The psychiatric profile of 112 individuals with Down syndrome (DS) and 85 with Williams syndrome (WS) was examined. The interactions between psychiatric symptom clusters and the effect of age were also investigated.Participants with WS had higher rates of psychiatric disorders, and, specifically, of Anxiety disorders and Psychosis than DS. However, the psychiatric profile changed by age, since Anxiety disorder was higher in individuals with WS compared to DS in young age, while Psychosis in old age. A relation between the occurrence of disorders, as Anxiety disorder and Mood Disorder, was found only in participants with WS. Moreover, distinct Anxiety and Behavior Disorder subtypes emerged between groups.Results indicate that the genetic etiology of ID differently affects the psychiatric characteristics of the groups and suggest the importance of a targeted psychiatric care for individuals with WS and DS.

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Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage

Cited by 108 publications

References 62 publications

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

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

Detecting Psychiatric Profile in Genetic Syndromes: A Comparison of Down Syndrome and Williams Syndrome

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