Neurodevelopmental disorders: 2021 update

One of the current challenges in the field of neurodevelopmental disorders (NDDs) is still to determine their underlying aetiology and risk factors. NDDs comprise a diverse group of disorders primarily related to neuro-developmental dysfunction including autism spectrum disorder (ASD), developmental delay, intellectual dis-ability (ID), and attention-deficit/hyperactivity disorder (ADHD) that may present with a certain degree of cognitive dysfunction and high prevalence of neuropsychiatric outcomes. Last year, advances in human ge-nomics have begun to shed light on the genetic architecture of these disorders and large-scale sequencing studies are starting to reveal mechanisms that range from unique genomic DNA methylation patterns (i.e. “episignatures”) to highly polygenic conditions. In addition, the contribution of de novo somatic mutations to neurodevelopmental diseases is being recognized. However, progressing from genetic findings to underlying neuropathological mechanisms has proved challenging, due to the increased resolution of the molecular and genetic assays. Advancement in modelling tools is likely to improve our understanding of the origin of neuro-developmental disorders and provide insight into their developmental mechanisms. Also, combined in vivo editing of multiple genes and single-cell RNA-sequencing (scRNA-seq) are bringing us into a new era of un-derstanding the molecular neuropathology of NDDs

Impaired spatial learning strategies and novel object recognition in mice haploinsufficient for the dual specificity tyrosine-regulated kinase-1A (Dyrk1A)

BACKGROUND: Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes. It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored. METHODOLOGY/PRINCIPAL FINDINGS: We used mice heterozygous for a Dyrk1A targeted mutation (Dyrk1A+/−) to investigate the implication of this gene in the cognitive phenotypes of monosomy 21. Performance of Dyrk1A+/− mice was assayed 1/ in a navigational task using the standard hippocampally related version of the Morris water maze, 2/ in a swimming test designed to reveal potential kinesthetic and stress-related behavioral differences between control and heterozygous mice under two levels of aversiveness (25°C and 17°C) and 3/ in a long-term novel object recognition task, sensitive to hippocampal damage. Dyrk1A+/− mice showed impairment in the development of spatial learning strategies in a hippocampally-dependent memory task, they were impaired in their novel object recognition ability and were more sensitive to aversive conditions in the swimming test than euploid control animals. CONCLUSIONS/SIGNIFICANCE: The present results are clear examples where removal of a single gene has a profound effect on phenotype and indicate that haploinsufficiency of DYRK1A might contribute to an impairment of cognitive functions and stress coping behavior in human monosomy 21

Behavioral Phenotyping for Down Syndrome in Mice

Down syndrome (DS) is the most frequent genetic cause of intellectual disability, characterized by alterations in different behavioral symptom domains: neurodevelopment, motor behavior, and cognition. As mouse models have the potential to generate data regarding the neurological basis for the specific behavioral profile of DS, and may indicate pharmacological treatments with the potential to affect their behavioral phenotype, it is important to be able to assess disease-relevant behavioral traits in animal models in order to provide biological plausibility to the potential findings. The field is at a juncture that requires assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this article, behavioral tests are described that are relevant to the domains affected in DS. A neurodevelopmental behavioral screen, the balance beam test, and the Multivariate Concentric Square Field test to assess multiple behavioral phenotypes and locomotion are described, discussing the ways to merge these findings to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed

uPA deficiency exacerbates muscular dystrophy in MDX mice

Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy

Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction

Accumulating evidence has suggested that neurotrophins participate in the pathophysiology of mood disorders. We have developed transgenic mice overexpressing the full-length neurotrophin-3 receptor TrkC (TgNTRK3) in the central nervous system. TgNTRK3 mice show increased anxiety-like behavior and enhancement of panic reaction in the mouse defense test battery, along with an increase in the number and density of catecholaminergic (tyrosine hydroxylase positive) neurons in locus coeruleus and substantia nigra. Furthermore, treatment of TgNTRK3 mice with diazepam significantly attenuated the anxiety-like behaviors in the plus maze. These results provide evidence for the involvement of TrkC in the development of noradrenergic neurons in the central nervous system with consequences on anxiety-like behavior and panic reaction. Thus, changes in TrkC expression levels could contribute to the phenotypic expression of panic disorder through a trophic effect on noradrenergic neurons in the locus coeruleus. Our results demonstrate that the elevated NT3-TrkC tone via overexpression of TrkC in the brain may constitute a molecular mechanism for the expression of anxiety and anxiety

Ten millennia of hepatitis B virus evolution

Hepatitis B virus (HBV) has been infecting humans for millennia and remains a global health problem, but its past diversity and dispersal routes are largely unknown. We generated HBV genomic data from 137 Eurasians and Native Americans dated between ~10,500 and ~400 years ago. We date the most recent common ancestor of all HBV lineages to between ~20,000 and 12,000 years ago, with the virus present in European and South American hunter-gatherers during the early Holocene. After the European Neolithic transition, Mesolithic HBV strains were replaced by a lineage likely disseminated by early farmers that prevailed throughout western Eurasia for ~4000 years, declining around the end of the 2nd millennium BCE. The only remnant of this prehistoric HBV diversity is the rare genotype G, which appears to have reemerged during the HIV pandemic

Efecto de dosis génica de DYRK1A (minibrain) en el proceso neurodegenerativo asociado al envejecimiento: Un estudio con ratones genéticamente modificados

[spa] El síndrome de Down (SD) se caracteriza por retraso mental, alteraciones motoras y la aparición de neuropatología tipo Alzheimer a edades tempranas. En el adulto con SD, los cambios neurodegenerativos presentan características diferenciales respecto a las observadas en la EA, pese a que comparte sus signos neuropatológicos. Estas diferencias se deben a que el proceso neurodegenerativo es consecuencia específica de las alteraciones en el neurodesarrollo y la plasticidad neuronal. La hipótesis del efecto de dosis génica en el síndrome de Down (SD) se basa en que el desequilibrio de dosis de genes específicos conduciría a niveles elevados de proteínas concretas con consecuencias fenotípicas. Sin embargo sólo algunos de ellos podrán tener consecuencias observables debido a posibles efectos compensatorios. Proponemos que Dyrk1A es uno de esos genes dosis-sensibles que en base a su patrón de expresión y a los sustratos de fosforilación identificados, podría participar en las alteraciones motoras, cognitivas y el proceso neuropatológico tipo EA en personas con SD a través de la afectación de la neuritogénesis y la neuroplasticidad. DYRK1A es un gen del cromosoma 21 que codifica para una serin-treonin quinasa de actividad dual que se expresa principalmente en médula espinal, cerebelo y núcleos motores relacionados y en estructuras prosencefálicas. Recientemente se ha implicado Dyrk1A en procesos de proliferación y diferenciación neuronal, en la regulación del ciclo celular, en aprendizaje y memoria y en procesos neurodegenerativos. El objetivo general de esta Tesis Doctoral consiste en determinar el papel del gen DYRK1A en el proceso degenerativo presente en el SD, tanto durante el neurodesarrollo como el asociado al envejecimiento y sus mecanismos patogenéticos, utilizando como aproximación experimental modelos de ratón genéticamente modificados con diferente dosis de este gen. Se aborda la descripción y caracterización del impacto de cambios en los niveles de expresión de Dyrk1A en el proceso neurodegenerativo y se estudian los aspectos mecanísticos que posiblemente subyacen a estos procesos, tanto a nivel neuroquímico, centrándonos en dos sistemas de neurotransmisión específicamente relacionados con función cognitiva, como a nivel celular, donde principalmente abordamos aspectos relacionados con neuritogénesis. Nuestros resultados implican a Dyrk1A en el deterioro asociado a la edad de la función motora y la memoria reciente, posiblemente a través de la alteración en los sistemas de neurotransmisión dopaminérgico y colinérgico, respectivamente. Además, sugieren que la sobreexpresión de Dyrk1A tiene consecuencias patogenéticas en los procesos de neuritogénesis, probablemente a través de la modulación de la dinámica del citoesqueleto de actina. Estas alteraciones podrían ser responsables de la falta de efectos cognitivo-conductuales observada en ratones transgénicos en el modelo den neuroplasticidad in vivo (enriquecimiento ambiental).[eng] Aging in Down syndrome (DS) is accompanied by neuropathological features of Alzheimer's disease (AD). In fact, a close relationship exists between both pathologies, so that DS has been proposed as a model to study the predementia stages of AD. The goals of this work were to understand the pathogenic mechanism of AD related to genetic environments associated with DS. To this end we focused on a candidate gene overexpressed in DS, Dyrk1A. Dyrk1A is a serin treonin kinase that has been proposed to participate in neurogenesis, cognitive processes and DS neuropathology. We analyzed the role of Dyrk1A in the altered structural plasticity, neurogenic processes and cognitive function during the AD progression in DS, using murine models with different Dyrk1A dosage. Behavioural, histological and neurochemical studies showed a role of Dyrk1A in AD in DS. Our results involved Dyrk1A in the age-associated decline of motor function and recent memory, possible through an alteration in the dopaminergic and colinergic neurotransmitter systems respectively. Moreover, Dyrk1A overexpression had pathogenetic consecuences in the neuritogenesis process, probably affecting the actin cytoskeleton dynamic regulation. Theses alterations might be responsables of the lack of cognitive/behavioural effects observed in transgenic mice in the in vivo neuroplasticity model

Building the future therapies for Down syndrome: the third international conference of the T21 research society

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6-9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer's disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar-ma-cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21

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

Altres ajuts: CERCA Programme/Generalitat de Catalunya ; The CIBER of Rare Diseases is an initiative of the ISCIIIIn 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