Research report
Mice with a fra-1 knock-in into the c-fos locus show impaired spatial but regular contextual learning and normal LTP

https://doi.org/10.1016/j.molbrainres.2004.07.004Get rights and content

Abstract

The immediate early gene c-fos is part of the AP-1 transcription factor complex, which is involved in molecular mechanisms underlying learning and memory. Mice that lack c-Fos in the brain show impairments in spatial reference and contextual learning, and also exhibit a reduced long-term potentiation of synaptic transmission (LTP) at CA3-to-CA1 synapses. In the present study, we investigated mice in which c-fos was deleted and replaced by fra-1 (c-fosfra-1 mice) to determine whether other members of the c-fos gene family can substitute for the functions of the c-fos gene. In c-fosfra-1 mice, both CA3-to-CA1 LTP and contextual learning in a Pavlovian fear conditioning task were similar to wild-type littermates, indicating that Fra-1 expression restored the impairments caused by brain-specific c-Fos depletion. However, c-Fos-mediated learning deficits in a reference memory task of the Morris watermaze were also present in c-fosfra-1 mice. These findings suggest that different c-Fos target genes are involved in LTP, contextual learning, and spatial reference memory formation.

Introduction

Learning and memory require long-lasting alterations in synaptic efficacy. Some of the underlying adaptive changes depend on gene expression and de novo protein synthesis [25], [32]. Activation of transcription factors is a critical step in the intracellular signaling cascades that lead to alterations in gene expression [6]. We recently demonstrated in mice that the transcription factor c-Fos is critically involved in specific forms of behavioral learning and in long-term potentiation of synaptic transmission (LTP) at hippocampal CA3-to-CA1 synapses [12], an electrophysiological learning paradigm [5].

c-Fos belongs to the same family of transcription factors as FosB and the Fos-related antigens 1 and 2 (Fra-1 and Fra-2) [1], [20]. Fos proteins form heterodimeric complexes with Jun proteins to constitute the transcription factor complex “activator protein-1 (AP-1)”. AP-1 complexes can bind to AP-1 recognition sequences found in a variety of target genes, thereby regulating gene expression [8], [16], [18], [29], [35]. The function of Fra-1 in the juvenile and adult central nervous system (CNS) is currently unknown, because fra-1 “knockout” mice die from severe developmental defects in utero at around embryonic day 10 [41]. However, by using “knock-in” mice in which c-Fos is deleted and replaced by Fra-1 (c-fosfra-1 mice), it has been shown that under physiological conditions Fra-1 can substitute for some, but not all c-Fos functions during development [11]. Fra-1 can replace c-Fos-dependent functions in the process of bone development and light-induced photoreceptor apoptosis. In contrast, Fra-1 fails to substitute for c-Fos in inducing target genes in fibroblasts.

It remained an open question if Fra-1 can also replace c-Fos-dependent functions in the brain. Mice that specifically lack c-Fos in the CNS (c-fosΔCNS mice) show impairments in specific memory-related features of the Morris watermaze task and Pavlovian fear conditioning [12]. This indicates a role of c-Fos in molecular processes underlying spatial and contextual learning [12]. Moreover, these behavioral learning deficits correlate with a reduced magnitude of hippocampal CA3-to-CA1 LTP. To investigate whether Fra-1 can substitute for c-Fos in these tasks, we subjected c-fosfra-1 mice to the same tests that were used to identify the learning deficits in mice lacking c-Fos. Our results show that Fra-1 can replace some, but not all, c-Fos functions in hippocampal synaptic plasticity and behavioral learning.

Section snippets

Animals and behavioral studies

Knock-in mice which express Fra-1 in place of c-Fos (c-fosfra-1 mice) were bred as described elsewhere [11]. All experiments were performed with 3–6 months old male mice in a mixed 129/Ola; C57BL/6 genetic background. 18 c-fosfra-1 mice and 17 control littermate mice were investigated. Mice were kept on a 12h:12h reversed light–dark cycle with light shifts at 6.00 and 18.00. Experiments were done during the animals' active phase. In the novel cage test, exploratory behavior was analyzed by

General, exploratory, and anxiety-related behavior is normal in c-fosfra-1 mice

c-fosfra-1 mice grew and mated normally and their overall behavior was indistinguishable from that of their littermates. More detailed behavioral tests on 3–6-month-old c-fosfra-1 mice revealed unaltered exploratory behavior in the novel cage analysis (Fig. 1A), and normal muscular strength and motor skills in a rotarod task (Fig. 1B). c-fosfra-1 mice also exhibited normal emotional behavior. In the dark–light-box, they had similar latencies to visit the anxiety-related light compartment, had

Discussion

Behavioral training and learning tasks leading to long-term memory formation cause an activation of Fos and Jun proteins forming AP-1 complexes with different subunit composition [17]. The detailed function of these AP-1 complexes is still unknown, but some AP-1 complexes may have overlapping or even redundant functions, activating the same target genes [20]. To investigate whether Fra-1 can functionally substitute for c-Fos in the CNS, c-fosfra-1 mice in which the c-fos gene is disrupted and

Acknowledgements

We thank C. Theussel and Dr. A. Bichl for maintaining our mouse colony. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (GA 427/4-2 to P.G.; and SFB 636 to P.G. and R.S.). The IMP is funded by Boehringer Ingelheim. We gratefully acknowledge the proof reading of the manuscript by Dr. C. Braeman and Prof. F.A. Henn.

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    Present address: Center for Neurobiology and Behavior, Columbia University, 701 W 168th, New York, NY 10032, USA.

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