Research reportLearning-facilitated long-term depression requires activation of the immediate early gene, c-fos, and is transcription dependent
Introduction
Bidirectional changes in synaptic strength may act in concert in the creation of a memory engram [1] and the polarity of induced plasticity may correlate to different qualities of memory [4], [5], [6], [7], [8]. In rodents, either test-pulse afferent stimulation or weak synaptic plasticity protocols, when given during a spatial learning task, facilitate the expression of persistent hippocampal long-term potentiation (LTP) or long-term depression (LTD), suggesting a tight association between synaptic plasticity and hippocampus-dependent learning [4], [5]. LTP is facilitated by de novo space, whereas LTD is facilitated by novel spatial context [4], [5], [6], [7]. This phenomenon is referred to as learning-facilitated synaptic plasticity: it describes the ability of hippocampal synapses to respond with long-lasting synaptic plasticity to the coupling of afferent stimulation with a spatial learning experience.
It is particularly striking that albeit in an input-specific manner, novel spatial experience facilitates LTP at selected synapses throughout the hippocampus. This is evident for example at the perforant path-dentate gyrus synapses [2], [8], the mossy fibre-CA3 synapse [7], the commissural associational-CA3 synapse [7] and the Schaffer collateral-CA1 synapse [2]. We postulate that this reflects a very robust phenomenon whereby selected synapses within the hippocampus are recruited into the encoding of spatial experience.
Intriguingly, when context because a salient aspect of spatial experience, LTD becomes involved [4], [5], [6], [8]. Whereas the learning of relatively discrete object-place configurations facilitates LTD in an input-specific manner at Schaffer collateral-CA1 [4], [6] and commissural associational-CA3 synapses [7], at perforant path-dentate gyrus and mossy fber-CA3 synapses LTD is facilitated by object-place configurations that relate more specifically to navigational or orientational information [7], [8]. This suggests that LTD may contribute contextual detail to spatial representations encoded by means of LTP.
The neuronal changes necessary for long-term storage of memory and the maintenance of long-term plasticity are likely to require new protein synthesis. Proteins encoded by immediate early genes (IEGs) may play an important role in the regulation of these processes. Among the best characterised IEG products are the Fos, Jun and Krox families of inducible transcription factors, which may initiate the transcription of target genes necessary for the consolidation of memory, and the effector IEG protein, Arc. All are induced shortly after induction of synaptic plasticity by stimulation of afferent fibres to the hippocampus [9], [10], [11], [12], [13], [14], [15]. Inhibition of c-jun kinase enhances LTD in vivo, inhibits depotentiation [16] and prevents inhibitory avoidance learning [72], whereas induction of both LTP and LTD trigger Arc expression in the hippocampus [17]. Raised levels of c-Fos transcription factor occur after extracellular stimulation [18] and after spatial learning [19]. The imaging of c-Fos is thus used as a marker of neuronal activity and is accepted as a method of visualising neuronal networks that are activated, for example, after learning tasks. This method is particularly useful in brain areas, such as the hippocampus where there is a very low level of basal c-Fos expression [20], [21], [22], [23]. This property (of low level expression) opens up the interesting possibility of using c-Fos as an assay to determine the relative contribution of hippocampal neurons to information encoding. It also offers the opportunity of assessing to what extent LTD (as a mechanism that reduces synaptic strength) can engage an immediate early gene in its putative process of enabling memory of spatial context.
Prevention of the induction of c-Fos in the hippocampus, impairs learning tasks [34] and expression increases following exposure to a variety of novel stimuli [24]. Interestingly, c-fos knock-out mice show impaired induction of LTP in the CA1 region [25]. These mice show deficits in learning of hippocampus-dependent tasks such as the water maze and contextual fear conditioning, but not of cued fear conditioning, which is known to be hippocampus-independent. Increased c-Fos protein expression has been reported after LTP and heterosynaptic LTD [9], [10], [26], [27], [28], [74] but no investigations have been conducted into the role of this immediate early gene in homosynaptic LTD or in LTD that is facilitated by learning. A prerequisite for learning-facilitated synaptic plasticity, and its presumed relevance for information storage, is that its regulatory mechanisms share similarities to the mechanisms regulating learning and memory. One such regulatory mechanism comprises reprogramming of gene transcription. This study therefore investigated and compared the role of c-fos activation in learning-facilitated LTD, along with the time-course of new gene transcription in this phenomenon.
Section snippets
Surgical preparation
Seven-to eight week old male Wistar rats were prepared as described previously [29]. Briefly, under sodium pentobarbital anaesthesia (“Nembutal”, 40 mg/kg, i.p.), animals underwent implantation of a monopolar recording and a bipolar stimulating electrode (made from 0.1 mm diameter teflon coated stainless steel wire). A drill hole was made (1 mm diameter) for the recording electrode (2.8 mm posterior to bregma, 1.8 mm lateral to the midline) and a second drill hole (1 mm diameter, 3.1 mm posterior to
Long-term depression induces elevations of c-Fos
In previous studies we have shown that low frequency stimulation (LFS) of afferent fibres to the CA1 region given as 1 Hz 600 times normally only elicits short-term depression (STD). This LFS protocol results in robust LTD that lasts for over 24 h, however, if it is coupled with exploration and learning of object-place configurations [2], [4], [6], [8]. Here, we compared hippocampi that had received test-pulses (n = 12) or weak LFS (n = 12) during novel spatial exploration of object-place
Discussion
The results of this study indicate that learning-facilitated LTD in the CA1 region of freely moving rats initiates expression of the immediate early gene c-fos. Furthermore, c-fos is required for the induction of LTD and for the retention of spatial learning experience. In line with this, we also observed that learning-facilitated LTD requires new gene transcription. Furthermore, we found that the contribution of c-fos to LTD is time-dependent: the activation of c-fos must be triggered during
Concluding comments
This study provides evidence that learning-facilitated LTD is immediate early gene and protein transcription-dependent and is intrinsically linked with spatial learning. Changes in c-Fos expression and protein transcription mediated by learning-facilitated LTD may thus reflect synaptic restructuring required for long-term information storage. The study offers novel insights into the mechanism underlying LTD and strongly supports a role for LTD in the cellular processes underlying memory and
Acknowledgments
We are grateful to Dr. Elisabeth Petrasch-Parwez, Jens Klausnitzer and Beate Krenzek for technical support and to Nadine Gomell for animal care. This work is supported by a grant from the German Research Foundation to DMV (SFB 874).
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