María Martínez de Lagrán

Erbb4 Deletion from Fast-Spiking Interneurons Causes Schizophrenia-like Phenotypes

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.

Fibrinogen drives dystrophic muscle fibrosis via a TGFβ/alternative macrophage activation pathway

In the fatal degenerative Duchenne muscular dystrophy (DMD), skeletal muscle is progressively replaced by fibrotic tissue. Here, we show that fibrinogen accumulates in dystrophic muscles of DMD patients and mdx mice. Genetic loss or pharmacological depletion of fibrinogen in these mice reduced fibrosis and dystrophy progression. Our results demonstrate that fibrinogen-Mac-1 receptor binding, through induction of IL-1beta, drives the synthesis of transforming growth factor-beta (TGFbeta) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGFbeta further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its alphavbeta3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy.

Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans

SCOPE Trisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit. METHODS AND RESULTS Here we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study. CONCLUSION We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.

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.

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.

Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A

Hippocampal adult neurogenesis disruptions have been suggested as one of the neuronal plasticity mechanisms underlying learning and memory impairment in Down syndrome (DS). However, it remains unknown whether specific candidate genes are implicated in these phenotypes in the multifactorial context of DS. Here we report that transgenic mice (TgDyrk1A) with overdosage of Dyrk1A, a DS candidate gene, show important alterations in adult neurogenesis including reduced cell proliferation rate, altered cell cycle progression and reduced cell cycle exit leading to premature migration, differentiation and reduced survival of newly born cells. In addition, less proportion of newborn hippocampal TgDyrk1A neurons are activated upon learning, suggesting reduced integration in learning circuits. Some of these alterations were DYRK1A kinase-dependent since we could rescue those using a DYRK1A inhibitor, epigallocatechin-3-gallate. Environmental enrichment also normalized DYRK1A kinase overdosage in the hippocampus, and rescued adult neurogenesis alterations in TgDyrk1A mice. We conclude that Dyrk1A is a good candidate to explain neuronal plasticity deficits in DS and that normalizing the excess of DYRK1A kinase activity either pharmacologically or using environmental stimulation can correct adult neurogenesis defects in DS.

Age-associated motor and visuo-spatial learning phenotype in Dyrk1A heterozygous mutant mice

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is a candidate gene for the Down syndrome neurological defects and may be involved in the progression of Alzheimers disease. Heterozygous mice for Dyrk1A (Dyrk1A+/-) exhibit decreased brain size, motor abnormalities and cognitive deficits in the adult. However, there is no information about the mutant phenotype in old ages. Here we analyze the impact of Dyrk1A dosage reduction on motor performance and hippocampal-dependent learning and memory in aged Dyrk1A+/- mice. Whereas motor tests showed marked alterations in traction ability, prehensile reflex and balance, heterozygous mice only present a slight impairment of visuo-spatial memory even though they show a robust decrease of CA1-CA3 and dentate gyrus cells.

Insights from Mouse Models to Understand Neurodegeneration in Down Syndrome

Individuals with trisomy 21, also known as Down syndrome (DS), develop a clinical syndrome including almost identical neuropathological characteristics of Alzheimers disease (AD) observed in non-DS individuals. The main difference is the early age of onset of AD pathology in individuals with DS, with hish incidence of clinical symptoms in the late 40- early 50 years of age. The neuropathology of AD in persons with DS is superimposed with the developmental abnormalities causing alterations of neuronal morphology and function. Despite the ubiquitous occurrence of AD neuropathology, clinical signs of dementia do not occur in all adults with DS even at older ages. Phenotype analysis of DS mouse models has revealed a differential age-related neurodegenerative pattern that correlates with specific biochemical and molecular alterations at the cellular level. In fact, several individual genes found in trisomy in DS have been functionally related to neuronal degeneration. Thus, mouse models overexpressing HSA21 gene(s) are fundamental to understand the neurodegenerative process in DS, as described in the present review. In addition, these models might allow to define and evaluate potential drug targets and to develop therapeutic strategies that may interfere or delay the onset of AD.

Functional implications of hippocampal adult neurogenesis in intellectual disabilities

The development of strategies capable to promote nervous system plasticity in adulthood is nowadays an important aim in neuroscience to improve not only cognitive abilities but also to ameliorate pathological dysfunctions. Several studies have demonstrated that adult neurogenesis is regulated by many physiological and pathological stimuli at almost every stage, from proliferation of neuronal precursors until integration and activation of newly formed neurons in the preexisting network. We review the process of generating functional neurons from precursors in the adult brain and its implications in intellectual disability disorders.