Abstract
Long-term potentiation of synaptic transmission (LTP) is one of the most studied manifestations of neuroplasticity and hippocampus is a classic object for the study of LTP mechanisms. The early phase of LTP depends on modifications of pre-existing synaptic proteins and the late phase of LTP needs de novo protein synthesis and gene expression. LTP-associated dynamics of the transcriptome and mechanisms of coupling synaptic activity with gene expression are intensively studied, but due to the vast complexity of the issue, abundance of unresolved questions remains in this field. The diversity of brain cell types is one of the main challenges. Until relatively recently, the analysis of molecular and genetic aspects of neuroplasticity has usually been confined to neuronal populations. Meanwhile, glia substantially contributes to synaptic transmission regulation. Astrocytes release various gliotransmitters, which modulate synaptic transmission and plasticity. S100B is one of those glia-derived regulatory factors. Learning in rats is accompanied by an increase in S100B expression in various brain regions including the hippocampus. The present study is focused on the neuroplasticity-associated S100B expression upregulation using long-term post-tetanic potentiation in rat hippocampal slices. In this chapter, we present a short review of published articles devoted to the analysis of gene expression during LTP formation including studies of the mechanism of LTP-associated S100B upregulation in hippocampus.
Keywords
- hippocampus
- CA1
- long-term potentiation
- gene expression
- p53
- S100B
- Bax
1. Introduction
Long-term alterations in the strength of synaptic transmission are a key physiological mechanism of learning and memory. To explain the formation of conditioned reflexes, Donald Hebb proposed that simultaneous or quasi-simultaneous discharge of two neuronal populations leads to the establishment of a functional connection between them [1]. The first attempts to find “Hebbian synapses” were undertaken by Jan Bureš [2, 3]. In his experimental model, sound or tactile sensory conditioned stimulus (CS), which slightly changed a frequency of neuronal discharges, was reinforced by a depolarizing current delivered through a recording microelectrode (unconditioned stimulus, US), which caused a strong neuronal discharge. In some neurons, responses to CS essentially increased after appropriate combination of CS and US. Interestingly, most significant effects were observed in the hippocampus [4], which is critical for acquisition and retrieval of some forms of memory [5, 6]. However, the persistence of plastic changes in this and other similar experimental models (tens of minutes) was relatively low in comparison with memory traces (reviewed in [7]).
The discovery of LTP in the hippocampus was a next essential step in the research of cellular and molecular mechanisms of synaptic plasticity [8]. LTP is the most studied form of plasticity associated with alterations in synaptic strength. A fairly common model of LTP is the increase in responses of postsynaptic neurons to stimulation of presynaptic fibers after high frequency stimulation (HFS)—tetanization or theta-stimulation—of the afferents. LTP is widely accepted as a neuronal mechanism of learning [9, 10, 11]. LTP that is dependent on glutamate receptors of NMDA type (NMDAR) is the most widespread in CNS and the most studied. LTP of perforant fiber-granular cell synapses in the dentate gyrus (DG) and LTP of Schaffer collateral (SC)-pyramidal cells in the area CA1 of the hippocampus are classic examples of this kind of LTP.
There are two main phases of LTP: the early phase lasting usually less than 1 hour and the late phase lasting several hours or longer (months). The early phase of LTP is based on post-translational modifications of pre-existing synaptic proteins and the late phase of LTP requires
2. LTP and neural activity-regulated genes
Identification of genes regulated by neuronal activity (ARGs) and clarification of the mechanisms of this regulation is an intensively developing research area. The families of transcription factors (TFs) thus far found to be critically involved in synaptic plasticity and memory formation include CREB, C/EBP, AP-1, Egr, and Rel/NFκB [21, 22]. Important advances in this field have been achieved by using microarrays and high-throughput sequencing. Hundreds of ARGs have been identified with complex expression dynamics after various kinds of stimulation: seizures, chemical stimulations, behavioural tasks, and HFS [20, 22, 23, 24]. Among transcriptomic studies of LTP in the hippocampus, works with induction of LTP in DG
Remarkably, the ARG lists from different authors showed little overlap [22]. One of the multiple reasons of this is a highly dynamic temporal regulation of the neuronal activity-regulated gene expression. For example, the level of
Temperature is also a factor influencing gene expression dynamics in brain slices. For example, differential expression of
In addition, the comparison of datasets generated in different studies is complicated by the limited access to original data. Only partial lists of ARGs, which passed arbitrarily designed significance filters, were often presented by authors. Nevertheless, differential expression of some genes is reproduced quite frequently. This is particularly true for early genes, association of which with LTP was already demonstrated in earlier works on this issue, such as
One of the most serious problems is a great diversity of the brain cell types, which is reflected in the diversity of their transcriptomes [34, 35]. For example, granular cells of the DG and pyramidal cells of the СА1-CA4 regions of the hippocampus differ in their transcriptomes [36], which can exhibit distinct dynamics after LTP induction [29]. Dorsal and ventral subregions of the rodent area CA1 also differ in their transcriptomes [37]. LTP induction alters gene expression not only in neurons but also in glial cells [20, 38, 39]. The role of glia in a structural, metabolic, and trophic support of neurons is well known. Undoubtedly, neuron life support is crucial for all brain functions including learning. For example, learning in rats is associated with an increase in extracellular lactate concentration in the brain, and disruption of lactate export out of astrocytes or import into neurons disturbs long-term memory and LTP in hippocampus [40]. In addition, glial cells directly participate in synaptic transmission [41, 42]. Astrocytes respond to neurotransmitters by an increase in intracellular calcium concentration followed by secretion of gliotransmitters modulating synaptic transmission and plasticity. Therefore, adequate research of LTP-associated gene expression must include an analysis of the cellular localization of observed phenomena, which is quite laborious. The task is somewhat easier, when ARGs are cell-specific.
One of such relatively cell-specific genes is
However,
To study the mechanisms of the neuroplasticity-associated
3. LTP-associated expression of S100B and other p53 target genes in rat hippocampal slices
The increase in
Transcription factor p53, well known as a key regulator of apoptosis, proved to be one of the TFs determining
The increase in p53 DNA-bound fraction was not associated with the increase in total p53 protein, which suggests p53 activation was due to post-translational modifications. The total p53 protein level even decreased in the area CA1 20 min after LTP induction, while
To confirm that LTP-associated p53 binding to
Thus, LTP in the area CA1 of the hippocampus is associated with transient p53 activation, which is one of the reasons of increased S100B synthesis. The decrease in p53 protein level after SC tetanization indicates that p53 negative regulators are activated soon after LTP induction. As mentioned above, p53 negative regulators include ubiquitin ligase Mdm2 and deacetylase Sirt1. Mdm2 negatively modulates p53 transcription activity, protein stability, and mRNA translation [64, 65]. Ubiquitination of lysine residues of p53 promotes its export from the nuclei followed by its degradation in proteasomes [66]. Thus, acetylation of lysine residues is an important element of p53 activation promoting its stabilization and import into the nucleus, while deacetylation decreases this activity and facilitates ubiquitination of lysine residues. Deacetylases controlling p53 acetylation status include NAD-dependent deacetylases, Sirt1 and Sirt2 [67, 68], and nonselective inhibitor of sirtuins tenovin-1 inhibits Mdm2-dependent degradation of p53 [69].
For evaluation of the contribution of Mdm2 and Sirt1 in tetanization-induced p53 protein downregulation, we studied the effects of Mdm2 inhibitor nutlin-3 and Sirt1 selective inhibitor EX-527 on the level of p53 protein after LTP induction. Inhibition of Mdm2 or Sirt1 fully prevented tetanization-induced decrease in p53 protein level [56, 57]. Therefore, Sirt1/Mdm2 tandem plays a key role in the p53 protein level decrease after LTP induction in the area CA1 of the hippocampus.
To reveal mechanisms of
It is an open question, furthermore, where NMDARs participating in
Mitogen-activated protein kinase (MAPK) p38 and 90 kDa ribosomal S6 kinases (RSKs) are also involved in
Then, how are RSKs activated during LTP in astrocytes in this case? There are alternative ways of RSK regulation. For example, in dendritic cells, RSKs can be activated through MAPK p38–MK2 [73]. Protein kinase MK2 is also expressed in microglia, neurons, and astrocytes [74]. Therefore, theoretically, Ca2+-dependent
Further, we questioned to what extent the short-term p53 activation in the early stage of LTP contributes to transcriptome dynamics. To estimate this contribution, we have studied the expression of several tens of genes that are directly or indirectly regulated by p53 30 min after induction of LTP [60]. The p53 activator nutlin-3 was used for the preliminary assessment of a putative participation of p53 in LTP-associated regulation of these genes. If p53 contribution to tetanization-induced expression of a gene is significant, nutlin-3 would be expected to occlude the effect of tetanization.
Based on this approach, we conclude that expression of several established p53 target genes is altered after LTP induction in a p53-independent way. They include
Some of these results are consistent with the data obtained previously by other researchers. For example, a neuronal activity-dependent decrease in the level of mRNA of the proapoptotic protein Bbc3 was observed in neuronal cultures [75, 76] and in mini-slices of areas CA3/CA1 of the hippocampus [20]. Moreover, Léveillé et al. [76] also concluded that this decrease did not depend on p53. Similarly, an increase in
It should be noted, however, that our suggestion that p53 participates in LTP-associated regulation of
4. Conclusion
Although p53 is known mostly as a key factor of apoptosis, its function is really much broader [78, 79] and sometimes prosurvival [80]. Intracellular regulatory cascades associated with LTP formation overlap with pathways regulating p53 activity, which indicates that, theoretically, p53 can be activated after LTP induction [58]. For example, active (phosphorylated) CREB directly interacts with p53, thus increasing its transcriptional activity [81].
During LTP formation in the area CA1 of the hippocampus, the increase in p53 transcriptional activity leads to
In addition, LTP-associated upregulation (perhaps, also p53-dependent) of the proapoptotic protein of Bcl2 family Bax is of special interest in the context of neuroplasticity. This protein is involved in a mechanism of NMDAR-dependent LTD in the area CA1 of the hippocampus. Bax-mediated limited activation of caspases leads to the internalization of AMPA-type glutamate receptors, thus weakening synaptic strength [83]. Therefore, as in the case with
Finally, at physiological doses, S100B possesses trophic and protective properties [43]. Btg2 is also capable of rendering neurons more resistant against excitotoxicity and promoting neuronal survival under stress [75]. Thus, LTP-associated alterations in the expression of p53 target genes are capable of mediating neuroprotective and trophic effects of neuronal activity.
Indeed, the answer to the question of how nuclear activity alters brain functioning will only be achieved by using a systems biology approach, in which the focus moves from single genes to gene network interactions [22]. Moreover, profound molecular changes following hippocampal slice preparation suggest the need for careful interpretation of gene expression regulation results when using the acute slice as a model to study physiological responses [38, 84]. In particular, it needs to be determined whether p53 is activated in the brain after LTP induction in vivo or in behavioural tasks such as learning. Further investigation of p53 and its target gene roles in neuroplasticity should be undertaken to improve existing knowledge of the regulation of gene expression in the brain and its role in plasticity and neuropathology.
Acknowledgments
This work was supported by the Russian Foundation for Basic Research (Grants nos. 09-04-00200-а, 12-04-00464-а, and 15-04-01753-a) and basic research project of the Russian Academy of Sciences (IV.35.1.5). The histological preparations were examined at the Shared Centre for Microscopic Analysis of Biological Objects of the Institute of Cytology and Genetics SB RAS. The authors are thankful to Dr. S.I. Baiborodin for technical support.
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