Abstract
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 in vivo. 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. Analysis 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 in vivo.
Highlights
Long-term potentiation (LTP) is widely regarded as a memory storage mechanism as it fulfils key properties of a mnemonic device
These data interpreted alongside the observation that Clathrinmediated endocytosis is a significantly regulated canonical pathway within the 24 h-LTP-related gene (LRG) set suggests that late phase LTPrelated gene expression may contribute to homeostatic glutamate receptor regulation
We have used Ingenuity Pathway Analysis and DAVID to interpret how the differentially expressed genes identified at 20 min, 5 h and 24 h post-LTP induction at perforant path synapses in vivo are related
Summary
Long-term potentiation (LTP) is widely regarded as a memory storage mechanism as it fulfils key properties of a mnemonic device. We have broadened our analysis to identify gene sets differentially regulated during the late phases of LTP (5 h and 24 h post-LTP induction), elucidating their associated canonical pathways, biological functions and clustering into gene networks. After normalization across all datasets and using a moderated paired ttest (Limma), an inclusive list of differentially expressed LRGs was produced for each time point using dual selection criteria (61.15 fold change; p,0.05) This analysis identified 190 differentially expressed genes (73% increased and 27% decreased) at 5 h postLTP induction, and 691 differentially expressed genes at 24 h post-LTP induction (31% increased and 69% decreased) (Figure 2; Table S1, S2). Functions across our full temporal range using the most current versions of the software
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