Dissecting the behaviour of transgenic mice: is it the mutation, the genetic background, or the environment?

Wolfer, David P; Lipp, Hans‐Peter

doi:10.1017/s0958067000020959

Cited by 99 publications

(80 citation statements)

References 25 publications

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“…While the discriminative stimulus properties of APDs may not be related to their antipsychotic efficacy, understanding APDs on both a behavioral and neurochemical level will help increase our understanding of the complex pharmacology of schizophrenia and lead to improved agents with greater therapeutic efficacy and reduced side effect liability. Also, the use of inbred strains of mice (e.g., C57BL/6 versus DBA/2, Porter et al 2008) offers strong advantages to investigations of the role of specific neurotransmitter receptor systems in the effects of pharmacological agents (see Holmes et al 2002;Crawley 2003;Wolfer and Lipp 2000). Establishing this model in C57BL/6 mice opens the door for the future behavioral phenotyping of transgenic and knockout mice in CLZ drug discrimination.…”

Section: Discussionmentioning

confidence: 99%

“…Characterization of this wild-type strain in behavioral assays such as drug discrimination is important, as the C57BL/6 mouse has become a standard inbred mouse strain used for breeding and is used as the background strain for many genetically engineered transgenic and knockout mice. Holmes et al (2002) have stated that the design and interpretation of studies on targeted gene mutations can be strengthened by fully characterizing the behavior of background mouse strains commonly used in such studies (see also, Banbury Conference on genetic background in mice 1997 ;Crawley 2003;Wolfer and Lipp 2000).…”

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confidence: 99%

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Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

et al. 2008

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Rationale The discriminative stimulus properties of the atypical antipsychotic drug (APD) clozapine (CLZ) have recently been studied in C57BL/6 mice, a common background strain for genetic alterations. However, further evaluation is needed to fully characterize CLZ's discriminative cue in this strain of mice. Objectives The objectives of the study were to confirm the previous findings using a shorter pretreatment time and to further characterize the receptor mechanisms mediating the discriminative stimulus properties of CLZ by testing APDs, selective ligands, and N-desmethylclozapine (CLZ's major metabolite) in C57BL/6 mice. Materials and methods C57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ (s.c.) from vehicle in a two-lever drug discrimination task.Results Generalization testing with CLZ yielded an ED 50 = 1.19 mg/kg. Substitution testing with APDs showed that the atypical APDs quetiapine, sertindole, zotepine, iloperidone, and melperone fully substituted for CLZ (≥80% CLZappropriate responding), but aripiprazole did not. The typical APDs chlorpromazine and thioridazine substituted for CLZ (fluphenazine and perphenazine did not). The serotonin (5-HT) 2A antagonist M100907 and the α 1 -adrenoceptor antagonist prazosin fully substituted for CLZ. The H 1 histaminergic antagonist pyrilamine, dopamine agonist amphetamine, and the selective serotonin reuptake inhibitor fluoxetine did not substitute for CLZ. While N-desmethylclozapine did not substitute for CLZ when tested alone, Ndesmethylclozapine plus a low dose of CLZ combined in an additive manner produced full substitution. Conclusions CLZ's discriminative cue in C57BL/6 mice is a "compound" cue mediated in part by antagonism of 5-HT 2A and α 1 receptors.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

et al. 2008

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“…The most likely explanation relates to differences in the genetic background of the mice in the two studies. It is well established that differences in genetic background of genetically modified mice can affect the outcome of behavioral studies (Crawley, 1996;Gerlai, 1996;Wolfer and Lipp, 2000). NR2A…”

Section: Discrimination Ratiomentioning

confidence: 99%

NMDA Receptor Subunit NR2A Is Required for Rapidly Acquired Spatial Working Memory But Not Incremental Spatial Reference Memory

Bannerman¹,

Niewoehner²,

Lyon³

et al. 2008

J. Neurosci.

179

120

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NMDA receptors (NMDARs) containing NR2A (1) subunits are key contributors to hippocampal long-term potentiation (LTP) induction in adult animals and have therefore been widely implicated in hippocampus-dependent spatial learning. Here we show that mice lacking the NR2A subunit or its C-terminal intracellular domain exhibit impaired spatial working memory (SWM) but normal spatial reference memory (SRM). Both NR2A mutants acquired the SRM version of the water maze task, and the SRM component of the radial maze, as well as controls. They were, however, impaired on a non-matching-to-place T-maze task, and on the SWM component of the radial maze. In addition, NR2A knock-out mice displayed a diminished spatial novelty preference in a spontaneous exploration Y-maze task, and were impaired on a T-maze task in which distinctive inserts present on the floor of the maze determined which goal arm contained the reward, but only if there was a discontiguity between the conditional cue and the place at which the reward was delivered. This dissociation of spatial memory into distinctive components is strikingly similar to results obtained with mice lacking glutamate receptor-A (GluR-A)-containing AMPA receptors, which support long-term potentiation expression. These results identify a specific role for a NMDAR-dependent signaling pathway that leads to the activation of a GluR-A-dependent expression mechanism in a rapidly acquired, flexible form of spatial memory. This mechanism depends on the C-terminal intracellular domain of the NR2A subunit. In contrast, the ability to associate a particular spatial location with the water maze escape platform or food reward is NR2A independent, as well as GluR-A independent.

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“…Although requiring twice the number of training days to achieve an equal level of performance in the Morris water maze as age-matched wild-type mice, young (6-8-wk), heterozygous BDNF knockout (KO) mice showed no deficits in memory retention (Linnarsson et al 1997). The potential contribution of the genetic background to the behavioral phenotype has always been a caveat of the knockout approach for the study of the neurobiology of behavior (Gingrich and Hen 2000;Wolfer and Lipp 2000). The studies reviewed here are no exception; they present, however, the critical controls performed in littermates of the same genetic background, and although not absolute, they represent significant comparative observations between siblings of different genotypes.…”

Section: Bdnf Signaling Is Necessary For Hippocampal-dependent Learningmentioning

confidence: 99%

From Acquisition to Consolidation: On the Role of Brain-Derived Neurotrophic Factor Signaling in Hippocampal-Dependent Learning

Tyler¹,

Alonso²,

Bramham³

et al. 2002

Learn. Mem.

627

398

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One of the most rigorously investigated problems in modern neuroscience is to decipher the mechanisms by which experience-induced changes in the central nervous system are translated into behavioral acquisition, consolidation, retention, and subsequent recall of information. Brain-derived neurotrophic factor (BDNF) has recently emerged as one of the most potent molecular mediators of not only central synaptic plasticity, but also behavioral interactions between an organism and its environment. Recent experimental evidence indicates that BDNF modulates synaptic transmission and plasticity by acting across different spatial and temporal domains. BDNF signaling evokes both short-and long-term periods of enhanced synaptic physiology in both pre-and postsynaptic compartments of central synapses. Specifically, BDNF/TrkB signaling converges on the MAP kinase pathway to enhance excitatory synaptic transmission in vivo, as well as hippocampal-dependent learning in behaving animals. Emerging concepts of the intracellular signaling cascades involved in synaptic plasticity induced through environmental interactions resulting in behavioral learning further support the contention that BDNF/TrkB signaling plays a fundamental role in mediating enduring changes in central synaptic structure and function. Here we review recent literature showing the involvement of BDNF/TrkB signaling in hippocampal-dependent learning paradigms, as well as in the types of cellular plasticity proposed to underlie learning and memory.

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Dissecting the behaviour of transgenic mice: is it the mutation, the genetic background, or the environment?

Cited by 99 publications

References 25 publications

Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

NMDA Receptor Subunit NR2A Is Required for Rapidly Acquired Spatial Working Memory But Not Incremental Spatial Reference Memory

From Acquisition to Consolidation: On the Role of Brain-Derived Neurotrophic Factor Signaling in Hippocampal-Dependent Learning

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