Research reportMice with a fra-1 knock-in into the c-fos locus show impaired spatial but regular contextual learning and normal LTP
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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2019, Biomedicine and PharmacotherapyCitation Excerpt :In the deficient c-fos mice, the brain display impairments in spatial reference and contextual learning, as well as decreased LTP of synaptic transmission at CA3-to-CA1 synapses [36]. Consistent with the previous study in the hippocampus [36], the current findings indicate that PS can decrease the expression of c-fos, which reversed by chronic treatment of ICA. Furthermore, CREB is a cellular transcription factor and regulate the transcription of downstream genes, including c-fos.
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2019, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Besides this, a wealth of observations indicates that the Fos and Jun family proteins can exert unique biological roles that cannot be compensated for by other family members in many, but not all, situations. Thus, gene knock-out- and knock-in experiments have shown that certain Fos and Jun proteins can show overlapping biological functions in particular cases [2,85–88]. This can only be explained by partly overlapping mechanistic actions, which are, however, still unclear.
Melatonin ameliorates amygdala-dependent emotional memory deficits in Tg2576 mice by up-regulating the CREB/c-Fos pathway
2017, Neuroscience LettersCitation Excerpt :c-fos, which represents the first identified IEG [6], is indispensable for the maintenance of normal synaptic plasticity. Mice that lack c-Fos in the brain exhibit impairments in spatial reference and contextual learning, as well as decreased long-term potentiation (LTP) of synaptic transmission at CA3-to-CA1 synapses [7,8]. Arc is another critical IEG that is only expressed in vertebrates [9]; it plays an essential role in the formation and consolidation of memories [10,11] and is also involved in synaptic remodeling and plasticity [12,13].
Adjuvant-induced arthritis induces c-Fos chronically in neurons in the hippocampus
2011, Journal of NeuroimmunologyCitation Excerpt :Transgenic mice that lack c-Fos in the brain have impaired spatial reference and contextual learning and exhibit a reduced long-term potentiation of synaptic transmission at CA3 to CA1 synapses (Fleischmann et al., 2003). In contrast, transgenic mice in which fra-1 was knocked into the c-fos locus showed impaired spatial, but regular contextual, learning and normal long-term potentiation responses (Gass et al., 2004). The redundancy of functions regulated by c-Fos and Fra-1 may result from c-Fos activation of fra-1 (Bergers et al., 1995; Matsuo et al., 2000).
The Multi-Gene Family of Transcription Factor AP-1
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Present address: Center for Neurobiology and Behavior, Columbia University, 701 W 168th, New York, NY 10032, USA.