Bridging Synaptic and Epigenetic Maintenance Mechanisms of the Engram

How memories are maintained, and how memories are lost during aging or disease, are intensely investigated issues. Arguably, the reigning theory is that synaptic modifications allow for the formation of engrams during learning, and sustaining engrams sustains memory. Activity-regulated gene expression profiles have been shown to be critical to these processes, and their control by the epigenome has begun to be investigated in earnest. Here, we propose a novel theory as to how engrams are sustained. We propose that many of the genes that are currently believed to underlie long-term memory are actually part of a “plasticity transcriptome” that underpins structural and functional modifications to neuronal connectivity during the hours to days following learning. Further, we hypothesize that a “maintenance transcriptome” is subsequently induced that includes epigenetic negative regulators of gene expression, particularly histone deacetylases. The maintenance transcriptome negatively regulates the plasticity transcriptome, and thus the plastic capability of a neuron, after learning. In this way, the maintenance transcriptome would act as a metaplasticity mechanism that raises the threshold for change in neurons within an engram, helping to ensure the connectivity is stabilized and memory is maintained

El defensor de Córdoba : diario católico: Año VI Número 1441 - 1904 julio 26

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 200

The immediate early gene Arc is not required for hippocampal long-term potentiation

Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early gene Arc, are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation, and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signaling. Here, we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock-out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 using Arc conditional KO mice did not have an effect on any form of LTP. Similarly, acute application of Arc antisense oligodeoxynucleotides had no effect on hippocampal CA1 LTP. Finally, the maintenance of in vivo LTP in the dentate gyrus of Arc KO mice was normal. We conclude that Arc is not necessary for hippocampal LTP and may mediate memory consolidation through alternative mechanisms. SIGNIFICANCE STATEMENT The immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modeled experimentally by induction of LTP, which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and may regulate memory storage through alternative mechanisms

Temporal Profiling of Gene Networks Associated with the Late Phase of Long-Term Potentiation <em>In Vivo</em>

<div><p>Long-term potentiation (LTP) is widely accepted as a cellular mechanism underlying memory processes. It is well established that LTP persistence is strongly dependent on activation of constitutive and inducible transcription factors, but there is limited information regarding the downstream gene networks and controlling elements that coalesce to stabilise LTP. To identify these gene networks, we used Affymetrix RAT230.2 microarrays to detect genes regulated 5 h and 24 h (n = 5) after LTP induction at perforant path synapses in the dentate gyrus of awake adult rats. The functional relationships of the differentially expressed genes were examined using DAVID and Ingenuity Pathway Analysis, and compared with our previous data derived 20 min post-LTP induction <em>in vivo</em>. This analysis showed that LTP-related genes are predominantly upregulated at 5 h but that there is pronounced downregulation of gene expression at 24 h after LTP induction. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040538#s2">Analysis</a> of the structure of the networks and canonical pathways predicted a regulation of calcium dynamics via G-protein coupled receptors, dendritogenesis and neurogenesis at the 5 h time-point. By 24 h neurotrophin-NFKB driven pathways of neuronal growth were identified. The temporal shift in gene expression appears to be mediated by regulation of protein synthesis, ubiquitination and time-dependent regulation of specific microRNA and histone deacetylase expression. Together this programme of genomic responses, marked by both homeostatic and growth pathways, is likely to be critical for the consolidation of LTP <em>in vivo.</em></p> </div

IPA network analysis at 5 h.

<p>The three highest scoring networks from LRG list are shown. Red, upregulated genes; green, downregulated genes. White open nodes, genes not present in LRG set but that interact with LRGs, as identified by the IPA Knowledge Base. A solid line denotes a direct functional interaction of the products of the two genes. A dotted line denotes an indirect interaction. An arrow indicates that a gene product “acts on” a target. *, Multiple affymetrix identifiers map to a single gene.</p

Induction of robust LTP by 50×400

<p> <b>Hz, 10 impulse trains (HFS) at perforant path dentate granule cell synapses.</b> Data are mean ± standard error (n = 5) for the fEPSP (A) and population spike (B). Inset waveforms are averages of 10 sweeps (5 min) for one animal, taken during baseline (1), 45–60 min (2) and 24 h (3) after HFS. Calibration bars: 5 ms, 5 mV.</p

Temporal relationship of LTP-regulated datasets.

<p>(A) Venn Diagram showing 3 datasets largely contain temporally specific genes. (B) Heatmap displaying average gene expression values (expressed as log fold change) of overlapping genes across the timepoints.</p

LTP-related gene expression 20 min, 5

<p> <b>h and 24 </b><b>h post-LTP induction.</b> Alterations in mRNA transcript number identified 20 min, 5 h and 24 h post-LTP, as detected using Affymetrix RAT 230 2.0 microarrays; note increase in proportion of downregulated genes at 24 h (dual selection criteria: fold change ≥1.15 or ≤0.85; p<0.05).</p

IPA network analysis at 24 h.

<p>The three highest scoring networks from the LRG list are shown. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040538#pone-0040538-g005" target="_blank">Figure 5</a> legend for further details.</p