Abstract
The long-lasting enhancement of synaptic effectiveness known as long-term potentiation (LTP) is considered to be the cellular basis of long-term memory. LTP elicits changes at the cellular and molecular level, including temporally specific alterations in gene networks. LTP can be seen as a biological process in which a transient signal sets a new homeostatic state that is “remembered” by cellular regulatory systems. Previously, we have shown that early growth response (Egr) transcription factors are of fundamental importance to gene networks recruited early after LTP induction. From a systems perspective, we hypothesized that these networks will show less stable architecture, while networks recruited later will exhibit increased stability, being more directly related to LTP consolidation. Using random Boolean network (RBN) simulations we found that the network derived at 24 h was markedly more stable than those derived at 20 min or 5 h post-LTP. This temporal effect on the vulnerability of the networks is mirrored by what is known about the vulnerability of LTP and memory itself. Differential gene co-expression analysis further highlighted the importance of the Egr family and found a rapid enrichment in connectivity at 20 min, followed by a systematic decrease, providing a potential explanation for the down-regulation of gene expression at 24 h documented in our preceding studies. We also found that the architecture exhibited by a control and the 24 h LTP co-expression networks fit well to a scale-free distribution, known to be robust against perturbations. By contrast the 20 min and 5 h networks showed more truncated distributions. These results suggest that a new homeostatic state is achieved 24 h post-LTP. Together, these data present an integrated view of the genomic response following LTP induction by which the stability of the networks regulated at different times parallel the properties observed at the synapse.
Highlights
Living cells are equipped with a robust and yet plastic analog system, which allows them to respond to environmental inputs
Gene Networks Recruited Earlier Following long-term potentiation (LTP) have a More Unstable Architecture To test the hypothesis that the gene networks induced more rapidly following LTP in vivo show a less stable architecture when compared to the network induced later, we have drawn on data from our previously published microarray data studies Ryan et al (2011, 2012)
We have presented a view of LTP as a biological process in which a transient signal sets a new homeostatic state that is “remembered” by the cellular systems
Summary
Living cells are equipped with a robust and yet plastic analog system, which allows them to respond to environmental inputs. From a genetic control perspective, it has been postulated that attractors in the gene and protein expression dynamics, which are the more stable position to which systems tends to evolve, define the cell’s character (Kauffman, 1969). The characterization of the structure of genetic networks from a dynamical perspective using different theoretical methods (Mestl et al, 1997) predicts two broad regimes. While robustness is a hallmark of homeostasis, it is reasonable to expect that transitions between cellular states require an enhanced sensitivity. In such scenario, a compromise between robustness and sensitivity could potentially be attained by a rewiring of the network or by the recruitment of different networks
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