Fig 4
Long-term memory. Time to reach the platform 8 days after the last learning session in the Morris water-maze (means ± SEM). Approximate locations of the YACs on chromosome 21 are indicated below the columns. * indicates significant difference compared to controls.
Source publication
Down syndrome occurs every 1/1000 births and is the most frequent genetic cause of mental retardation. The genetic substrate of Down syndrome, an extra chromosome 21, was discovered by Lejeune, half-a-century ago, and the chromosome has been fully sequenced, although the gene(s) implicated in the mental retardation observed with the syndrome are st...
Contexts in source publication
Context 1
... global ANOVA showed a significant differ- ence in the five groups for long-term memory (F = 11.71, p < 0:001), F7 and E6 did not differ from one another but both differed from E8, G6 and the non-transgenics as shown in Figure ...
Context 2
... memory deficits characterize persons with DS ( Brown et al., 2003;Clark and Wilson, 2003;Hodapp et al., 1999;Raz et al., 1995). We measured long-term memory performance, eight days after the last learning session. The F7 and E6 mice spent more time reaching the platform at the recall session (Fig. 4), showing they did not accu- rately remember the location of the ...
Similar publications
Using paired-end sequences from bacterial artificial chromosomes, we have constructed high-resolution synteny and rearrangement breakpoint maps among human, mouse, and rat genomes. Among the >300 syntenic blocks identified are segments of over 40 Mb without any detected interspecies rearrangements, as well as regions with frequently broken synteny...
Modern sugarcane (Saccharum spp.) is an important grass that contributes 60% of the raw sugar produced worldwide and has a high biofuel production potential. It was created about a century ago through hybridization of two highly polyploid species, namely S. officinarum and S. spontaneum. We investigated genome dynamics in this highly polyploid cont...
The barley stem rust resistance genes Rpg1 and rpg4 were mapped in barley on chromosomes 1P and 7M, respectively and the syntenous rice chromosomes identified as 6P and 3P by mapping common probes in barley and rice. Rice yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC) and cosmid clones were used to isolate probes mapping t...
Fragmentary conservation of synteny has been reported between map-anchored Prunus sequences and Arabidopsis. With the availability of genome sequence for fellow rosid I members Populus and Medicago, we analyzed the synteny between Prunus and the three model genomes. Eight Prunus BAC sequences and map-anchored Prunus sequences were used in the compa...
Citations
... Unlike plasmid pronuclear injection, large genomic transgenes are more likely to produce copy number dependent transgene expression that is independent of positional effects and better recapitulate endogenous gene expression patterns (Chandler et al., 2007;Giraldo and Montoliu, 2001). YAC models have been developed and analyzed to understand the contribution of some DS genes, including DYRK1A, to cognitive function and other features (Branchi et al., 2004;Chabert et al., 2004;Guedj et al., 2009;Rachidi et al., 2007;Roubertoux et al., 2006;Sebrie et al., 2008;Smith et al., 1995. The use of BAC transgenesis to model DS is technically complex and time-consuming. ...
The genotype-phenotype relationship and the physiopathology of Down Syndrome (DS) have been explored in the last 20 years with more and more relevant mouse models. From the early age of transgenesis to the new CRISPR/CAS9-derived chromosomal engineering and the transchromosomic technologies, mouse models have been key to identify homologous genes or entire regions homologous to the human chromosome 21 that are necessary or sufficient to induce DS features, to investigate the complexity of the genetic interactions that are involved in DS and to explore therapeutic strategies. In this review we report the new developments made, how genomic data and new genetic tools have deeply changed our way of making models, extended our panel of animal models, and increased our understanding of the neurobiology of the disease. But even if we have made an incredible progress which promises to make DS a curable condition, we are facing new research challenges to nurture our knowledge of DS pathophysiology as a neurodevelopmental disorder with many comorbidities during ageing.
... Unlike plasmid pronuclear injection, large genomic transgenes are more likely to produce copy number dependent transgene expression that is independent of positional effects and better recapitulate endogenous gene expression patterns (Chandler et al., 2007;Giraldo and Montoliu, 2001). YAC models have been developed and analyzed to understand the contribution of some DS genes, including DYRK1A, to cognitive function and other features (Branchi et al., 2004;Chabert et al., 2004;Guedj et al., 2009;Rachidi et al., 2007;Roubertoux et al., 2006;Sebrie et al., 2008;Smith et al., 1995. The use of BAC transgenesis to model DS is technically complex and time-consuming. ...
... A number of studies have found that genes carried by MMU 10 and MMU 17 do not contribute to the neurological and cognitive disorders associated with Down syndrome, but that mice carrying a triple copy of MMU16 do present the deficits (Roubertoux and Carlier 2010 ). We explored the D21S17-ETS2 region located on MMU16, the region known to encompass 19 genes which, when triplicated, are involved in trisomy 21 (Chabert et al. 2004 ;Smith et al. 1995Smith et al. , 1997. Partial triplication of the D21S17-ETS2 region was performed using Smith's model using four different segmental trisomic strains of mice with a fragment covering the region. ...
... Partial triplication of the D21S17-ETS2 region was performed using Smith's model using four different segmental trisomic strains of mice with a fragment covering the region. One strain with four triplicated genes was severely impaired, while the other strains triplicating a variable number of genes were less severely affected (Chabert et al. 2004 ;Roubertoux et al. 2005Seregaza et al. 2006 ). The question is: "Does each trisomic strain contributes a significant percentage of the impairment produced by the triplication of MMU16?" ...
With high prevalence (between 10 and 20 per live 1000 births), intellectual disability weighs on the public health budget and is a major concern to the patient’s relatives. Organism models of intellectual disability provide information on the causes and mechanisms and, most importantly, can provide markers for treatments. This chapter examines the contribution of organism models to the knowledge of intellectual disability in translational research. It also defines criteria for assessing whether a model fits a given disease (identical etiology, similar molecular signature, pathways, and clinical signs). This chapter considers the practicality of a transverse approach in light of the latest organism models and discusses the benefits of combining it with a top-down strategy.
... To address this, learning, plasticity, and GIRK signaling were investigated in a mouse model with a selective overexpression of GIRK2 (28E6/67; Smith, Zhu, Zhang, Cheng, & Rubin, 1995). 28E6/67 (GIRK2 trisomy) mice exhibit impaired hippocampal-dependent spatial memory (Chabert et al., 2004) and associative learning (Cooper et al., 2012). These deficits were accompanied by increased GIRK currents mediated by A 1 receptor activation, but not GABA B receptors, suggesting that the extra copy of Kcnj6 translates into increased GIRK channel expression and activity for channels coupled to some, but not all, GPCRs (Cooper et al., 2012). ...
The ability of drug-associated cues to reinitiate drug craving and seeking, even after long periods of abstinence, has led to the hypothesis that addiction represents a form of pathological learning, in which drugs of abuse hijack normal learning and memory processes to support long-term addictive behaviors. In this chapter, we review evidence suggesting that G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels are one mechanism through which numerous drugs of abuse can modulate learning and memory processes. We will examine the role of GIRK channels in two forms of experience-dependent long-term changes in neuronal function: homeostatic plasticity and synaptic plasticity. We will also discuss how drug-induced changes in GIRK-mediated signaling can lead to changes that support the development and maintenance of addiction.
... The Down syndrome critical region (DSCR) of chromosome 21 contains several genes, including KCNJ6, which encodes the GIRK2 subunit (Toyoda et al., 2002). Transpolygenic mice carrying extra copies of chromosome 21 fragments covering the DSCR showed cognitive disabilities in most tests of the Morris water-maze and in the altered context stage in fear-conditioning tests (Chabert et al., 2004). The presence of KCNJ6 in this region and the overexpression of GIRK2 and enhanced GABA B Rdependent signaling may contribute to some of the mental disabilities in Down syndrome, as reviewed in Cramer, Best, Stoffel, Siarey, and Galdzicki (2010). ...
G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson's disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders.
... While available evidence suggests that enhanced GIRKdependent signaling is detrimental to cognition and normal synaptic plasticity (32,(34)(35)(36)(37), less is known concerning the impact of diminished neuronal GIRK channel activity on these processes. Accordingly, we investigated the contribution of GIRK channels to associative learning and memory using three loss-of-function models. ...
... Mouse models exhibiting enhanced GIRK-dependent signaling show altered learning and memory (19,(32)(33)(34). Neither the behavioral impact of GIRK channel ablation nor the cellspecific contribution of GIRK channels to hippocampaldependent cognition, however, has been examined. ...
Background:
Cognitive dysfunction occurs in many debilitating conditions including Alzheimer's disease, Down syndrome, schizophrenia, and mood disorders. The dorsal hippocampus is a critical locus of cognitive processes linked to spatial and contextual learning. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels, which mediate the postsynaptic inhibitory effect of many neurotransmitters, have been implicated in hippocampal-dependent cognition. Available evidence, however, derives primarily from constitutive gain-of-function models that lack cellular specificity.
Methods:
We used constitutive and neuron-specific gene ablation models targeting an integral subunit of neuronal GIRK channels (GIRK2) to probe the impact of GIRK channels on associative learning and memory.
Results:
Constitutive Girk2(-/-) mice exhibited a striking deficit in hippocampal-dependent (contextual) and hippocampal-independent (cue) fear conditioning. Mice lacking GIRK2 in gamma-aminobutyric acid neurons (GAD-Cre:Girk2(flox/flox) mice) exhibited a clear deficit in GIRK-dependent signaling in dorsal hippocampal gamma-aminobutyric acid neurons but no evident behavioral phenotype. Mice lacking GIRK2 in forebrain pyramidal neurons (CaMKII-Cre(+):Girk2(flox/flox) mice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII-Cre(+):Girk2(flox/flox) mice also displayed a selective impairment in contextual fear conditioning, as both cue fear and spatial learning were intact in these mice. Finally, loss of GIRK2 in forebrain pyramidal neurons correlated with enhanced long-term depression and blunted depotentiation of long-term potentiation at the Schaffer collateral/cornu ammonis 1 synapse in the dorsal hippocampus.
Conclusions:
Our data suggest that GIRK channels in dorsal hippocampal pyramidal neurons are necessary for normal learning involving aversive stimuli and support the contention that dysregulation of GIRK-dependent signaling may underlie cognitive dysfunction in some disorders.
... A general profile appears with relative strength in associative tasks, difficulty in responding by new strategies to new conditions, poor long-term memory and attention difficulties (see Roubertoux and Kerdelhué 2006;Roubertoux and Carlier 2009). The psychological profile deduced from clinical studies has been used as framework for mouse models of trisomy 21 ( Chabert et al. 2004). An exhaustive review of the studies ( Sérégaza et al. 2006;Roubertoux and Carlier, 2009) showed that most of them attempted to adjust the model organism to the human profile. ...
Scientific literature on atypical development is so vast that a systematic review could not fit in some 40 pages; therefore, we had to make choices. First, we have limited our presentation to intellectual disability (ID), leaving aside behavioral and psychiatric disorders. After defining ID, the main causes are presented (genetic and environmental) with special emphasis on gene–environment correlations and/or interactions. We then selected two genetic disorders linked to ID (Phenylketonuria and Fragile X) to present both the research methodologies and the type of findings, before discussing the contribution of cross-syndrome comparisons. To uncover a causal link between genetic events and a behavioral phenotype, it is often essential to use model organisms. The advantage of such models, plus the requirements and limitations involved in their use, are presented before concluding the chapter
... sub-band allowed to suggest that most signs of the syndrome, including intellectual disability, depend on the expression of this region. For this reason, is considered a critical region for DS, receiving the name of Down syndrome critical region (DSCR) (Chabert et al., 2004;Rachidi & Lopes, 2008). However, it must be taken into consideration that the triplication of this region is regarded necessary but not sufficient to explain the phenotypic features of DS . ...
Down syndrome is an autosomal trisomy that traditionally has been studied independently from fields such as medicine, biology or psychology. In this article, we intend to go further and incorporate a multidisciplinary approach that includes, on the one hand, the main findings of these disciplines and, the theories, that attempt to explain the complex relationships that occur between such findings. With this aim, we review the progress that has been made in the field of genetics, neuroanatomy and neurochemistry in relation to this syndrome, as well as the explanations that have been developed to try to understand the neuropsychological profile associated with this condition. We believe that the incorporation of this perspective will help achieve an overview of the psychobiological correlates of Down syndrome.
... The role of GIRK2 in cognition has been supported by studies showing that rodents lacking GIRK1 and GIRK4 subunits present altered learning and memory (Kourrrich et Wickman et al., 2000;Lu¨scher and Slesinger, 2010). Furthermore, mice carrying the KCNJ6/GIRK2 gene in trisomy show deficits in hippocampus-dependent learning and memory, altered depotentiation and increased long-term synaptic depression, with intact long-term potentiation (Chabert et al., 2004;Cooper et al., 2012). In TS mice, the presence of an extra KCNJ6/GIRK2 gene copy has been shown to lead to elevation in GIRK2 mRNA throughout the brain and in particular the hippocampus (Harashima et al., 2006a), a structure involved in learning and memory processes. ...
The Ts65Dn (TS) mouse model of Down syndrome (DS) displays a number of behavioral, neuromorphological and neurochemical phenotypes of the syndrome. Altered GABAergic transmission appears to contribute to the mechanisms responsible for the cognitive impairments in TS mice. Increased functional expression of the trisomic gene encoding an inwardly rectifying potassium channel, subfamily J, member 6 (KCNJ6) has been reported in DS and TS mice, along with the consequent impairment in GAB Aergic function. Partial display of DS phenotypes in mice harboring a single trisomy of Kcnj6 provides compelling evidence for a functional role of increased channel expression in some of the abnormal neurological phenotypes found in DS. Notably, the antiepileptic drug (AED) ethosuximide (ETH), but not other AEDs such as gabapentin (GAB), is known to inhibit KCNJ6 channels in mice. Here, we report the effect of chronic ETH and GAB on the behavioral and cognitive phenotypes of TS and disomic control (CO) mice. Neither drug significantly affected sensorimotor abilities, motor coordination or spontaneous activity in TS and CO mice. Also, ETH and GAB did not induce anxiety in the open field or plus maze tests, did not alter performance in the Morris water maze, and did not affect cued - or context - fear conditioning. Our results thus suggest that KCNJ6 may not be a promising drug target candidate in DS. As a corollary, they also show that long-term use of ETH and GAB is devoid of adverse behavioral and cognitive effects.
... Nevertheless, Chabert et al. (20) did report impaired long-term memory in the Morris water maze task, suggesting hippocampal-dependent memory dysfunction that corresponds with the current findings. The current results are discordant with previous reports (20), indicating this line of mice as displaying normal contextual fear conditioning, yet methodological differences in the conditioning paradigm, apparatus, and freezing quantification method between the present study and the previous report may account for this discrepancy. Furthermore, these methodological considerations may also account for the discrepancies in cued fear conditioning; Ts65Dn exhibited deficits in cued fear conditioning (31), but GIRK2 triploid mice freezing in response to the cue did not differ from those of GIRK2 diploid mice, suggesting intact amygdala-dependent learning and memory. ...
G protein-activated inwardly rectifying K+ channels (GIRK) generate slow inhibitory postsynaptic potentials in the brain via G(i/o) protein-coupled receptors. GIRK2, a GIRK subunit, is widely abundant in the brain and has been implicated in various functions and pathologies, such as learning and memory, reward, motor coordination, and Down syndrome. Down syndrome, the most prevalent cause of mental retardation, results from the presence of an extra maternal chromosome 21 (trisomy 21), which comprises the Kcnj6 gene (GIRK2). The present study examined the behaviors and cellular physiology properties in mice harboring a single trisomy of the Kcnj6 gene. Kcnj6 triploid mice exhibit deficits in hippocampal-dependent learning and memory, altered responses to rewards, hampered depotentiation, a form of excitatory synaptic plasticity, and have accentuated long-term synaptic depression. Collectively the findings suggest that triplication of Kcnj6 gene may play an active role in some of the abnormal neurological phenotypes found in Down syndrome.
