Behavioral phenotyping of Nestin-Cre mice: Implications for genetic mouse models of psychiatric disorders

Giusti, Sebastián; Vercelli, Claudia Alejandra; Vogl, Annette M.; Kolarz, Adam; Pino, Natalia S.; Deussing, Jan M.; Refojo, Damián

doi:10.1016/j.jpsychires.2014.04.002

Cited by 83 publications

(77 citation statements)

References 66 publications

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“…Even commonly used Cre driver lines, however, can have unexpected Cre activity patterns or show complicating phenotypes (Harno et al, 2013; Heffner et al, 2012; Schmidt-supprian and Rajewsky, 2007). For example, a Nestin-Cre mouse line ( Tg(Nes-cre)1Kln ), is one of the most commonly used Cre driver lines in the neuroscience field, but reports have revealed unexpected Cre expression in many tissues outside the central nervous system and a significant metabolic and behavioral phenotype in Nestin-Cre mice (Declercq et al., 2015; Giusti et al, 2014; Harno et al, 2013). These factors greatly complicate the interpretation of the derived phenotypes, and reduce the utility of this approach.…”

Section: Introductionmentioning

confidence: 99%

Generation and analysis of an improved Foxg1-IRES-Cre driver mouse line

Kawaguchi

Sahara

Zembrzycki

et al. 2016

Developmental Biology

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Foxg1 expression is highly restricted to the telencephalon and other head structures in the early embryo. This expression pattern has been exploited to generate conditional knockout mice, based on a widely used Foxg1-Cre knock-in line (Foxg1tm1(cre)Skm), in which the Foxg1 coding region was replaced by the Cre gene. The utility of this line, however, is severely hampered for two reasons: (1) Foxg1-Cre mice display ectopic and unpredictable Cre activity, and (2) Foxg1 haploinsufficiency can produce neurodevelopmental phenotypes. To overcome these issues, we have generated a new Foxg1-IRES-Cre knock-in mouse line, in which an IRES-Cre cassette was inserted in the 3′UTR of Foxg1 locus, thus preserving the endogenous Foxg1 coding region and un-translated gene regulatory sequences in the 3′UTR, including recently discovered microRNA targeting sites. We further demonstrate that the new Foxg1-IRES-Cre line displays consistent Cre activity patterns that recapitulated the endogenous Foxg1 expression at embryonic and postnatal stages without causing defects in cortical development. We conclude that the new Foxg1-IRES-Cre mouse line is a unique and advanced tool for studying genes involved in the development of the telencephalon and other Foxg1-expressing regions starting from early embryonic stages.

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Section: Introductionmentioning

confidence: 99%

Generation and analysis of an improved Foxg1-IRES-Cre driver mouse line

Kawaguchi

Sahara

Zembrzycki

et al. 2016

Developmental Biology

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“…However, mice carrying the Nestin-Cre transgene alone (NesCre) have previously been associated with metabolic issues [28] as well as with potential deficits in learning [29], although that same study found that the deficit was rather specific to fear conditioning (freezing responses) and did not carry over to other kinds of learning. Nevertheless, given these previous indications, we conducted a further control study with 12 NesCre and 12 wild-type (WT) mice using the exact same experimental protocol as employed before.…”

Section: Resultsmentioning

confidence: 99%

“…Crossbred Ca v 1.2 fl/fl mice homozygous for the floxed Ca v 1.2 allele but lacking Cre recombinase expression (genotype: Ca v 1.2 L2/L2, Nestin-Cre -/-), and thus not suffering calcium channel loss, served as primary controls within the experiment. To rule out that observed learning differences between these 2 groups were not attributable to metabolic [28] or other potential factors [29] associated with the expression of Cre recombinase in the Ca v 1.2 NesCre group, we assessed performance of 2 additional control groups: animals with a heterozygous transgene expressing Cre recombinase under the control of a Nestin promoter without loxP-flanked Ca v 1.2 alleles (NesCre; genotype: Ca v 1.2 +/+, Nestin-Cre +/-) and pure wild-type animals (WT; genotype: Ca v 1.2 +/+, Nestin-Cre -/-).…”

Section: Methodsmentioning

confidence: 99%

CACNA1C gene regulates behavioral strategies in operant rule learning

et al. 2017

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Behavioral experiments are usually designed to tap into a specific cognitive function, but animals may solve a given task through a variety of different and individual behavioral strategies, some of them not foreseen by the experimenter. Animal learning may therefore be seen more as the process of selecting among, and adapting, potential behavioral policies, rather than mere strengthening of associative links. Calcium influx through high-voltage-gated Ca2+ channels is central to synaptic plasticity, and altered expression of Cav1.2 channels and the CACNA1C gene have been associated with severe learning deficits and psychiatric disorders. Given this, we were interested in how specifically a selective functional ablation of the Cacna1c gene would modulate the learning process. Using a detailed, individual-level analysis of learning on an operant cue discrimination task in terms of behavioral strategies, combined with Bayesian selection among computational models estimated from the empirical data, we show that a Cacna1c knockout does not impair learning in general but has a much more specific effect: the majority of Cacna1c knockout mice still managed to increase reward feedback across trials but did so by adapting an outcome-based strategy, while the majority of matched controls adopted the experimentally intended cue-association rule. Our results thus point to a quite specific role of a single gene in learning and highlight that much more mechanistic insight could be gained by examining response patterns in terms of a larger repertoire of potential behavioral strategies. The results may also have clinical implications for treating psychiatric disorders.

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“…The accumulation of proteins and its consequences on neuronal functionality has been the focus of many neurodegenerative disease‐related studies (Chishti et al, ; Hardy and Selkoe, ; Dauer and Przedborski, ; Ross and Tabrizi, ; Cohen et al, ). Additionally, several studies have already reported Cre‐mediated side‐effects (Schmidt‐Supprian and Rajewsky, ; Giusti et al, ), yet, to the best of our knowledge, the possibility of detrimental consequences of lacZ expression has not been considered so far. Therefore, we here analyzed the consequences of lacZ expression for two opposing neuronal sub‐populations in the mouse forebrain, cortical glutamatergic and GABAergic neurons.…”

Section: Discussionmentioning

confidence: 99%

“…The Cre/loxP system itself has been previously investigated regarding potential side-effects and has been found to be not always inert (Schmidt-Supprian and Rajewsky, 2007;Giusti et al, 2014a). Similarly, in vitro expression of another reporter protein, namely yellow fluorescent protein (YFP), has been shown to induce neurodegenerative-like effects including altered neuronal morphology (Comley et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Beware of your Cre‐Ation: lacZ expression impairs neuronal integrity and hippocampus‐dependent memory

et al. 2016

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Expression of the lacZ-sequence is a widely used reporter-tool to assess the transgenic and/or transfection efficacy of a target gene in mice. Once activated, lacZ is permanently expressed. However, protein accumulation is one of the hallmarks of neurodegenerative diseases. Furthermore, the protein product of the bacterial lacZ gene is ß-galactosidase, an analog to the mammalian senescence-associated ß-galactosidase, a molecular marker for aging. Therefore we studied the behavioral, structural and molecular consequences of lacZ expression in distinct neuronal sub-populations. lacZ expression in cortical glutamatergic neurons resulted in severe impairments in hippocampus-dependent memory accompanied by marked structural alterations throughout the CNS. In contrast, GFP expression or the expression of the ChR2/YFP fusion product in the same cell populations did not result in either cognitive or structural deficits. GABAergic lacZ expression caused significantly decreased hyper-arousal and mild cognitive deficits. Attenuated structural and behavioral consequences of lacZ expression could also be induced in adulthood, and lacZ transfection in neuronal cell cultures significantly decreased their viability. Our findings provide a strong caveat against the use of lacZ reporter mice for phenotyping studies and point to a particular sensitivity of the hippocampus formation to detrimental consequences of lacZ expression. © 2016 Wiley Periodicals, Inc.

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Behavioral phenotyping of Nestin-Cre mice: Implications for genetic mouse models of psychiatric disorders

Cited by 83 publications

References 66 publications

Generation and analysis of an improved Foxg1-IRES-Cre driver mouse line

Generation and analysis of an improved Foxg1-IRES-Cre driver mouse line

CACNA1C gene regulates behavioral strategies in operant rule learning

Beware of your Cre‐Ation: lacZ expression impairs neuronal integrity and hippocampus‐dependent memory

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