Memory HQ: the possible central role of the epigenome in maintaining LTP.

learning;memory;Epigenetics;long-term potentiation

Kyrke-Smith, Madeleine ; Williams, Joanna M. ; Abraham, Wickliffe C.

University of Otago

关键词: learning;    memory;    Epigenetics;    long-term potentiation;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/7192/1/Kyrke-SmithMadeleine2016PhD.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

Plasticity mechanisms such as long-term potentiation (LTP) are believed to underlie the formation and maintenance of memories. LTP induction stimulates downstream signalling pathways that lead to changes in gene expression which are critical to the maintenance of LTP. However, how these changes allow LTP to persist is not currently understood. The epigenetic mechanism, histone acetylation, has been shown to be regulated over the first few hours after LTP induction in vitro. Indeed, inhibition of enzymes that negatively regulate histone acetylation, histone deacetylase 1 and 2 (HDAC1 and HDAC2), enhances LTP induced in vitro, suggesting that HDAC inhibition supports LTP persistence. However, HDAC1 and HDAC2 have themselves been shown to be upregulated 5 – 24 h post-LTP induction in vivo and the effect of inhibiting HDACs over these later time-points has not been investigated. We aimed to identify if changes in HDAC activity played a role in LTP persistence over weeks, a timeframe which can not be studied when LTP is induced in vitro. We found that the activity of both HDAC1 and HDAC2 was upregulated 20 min post-LTP induction, returning to near baseline by 5 h and that HDAC1 activity was subsequently upregulated 12 h post-LTP induction. Interestingly, inhibition of the initial increase in HDAC activity, using the HDAC inhibitor Trichostatin A (TSA), had no effect on the induction of LTP, nor on the overall persistence of LTP. However, TSA did enhance the magnitude of LTP expressed between 12 h and 7 days post-induction. This time period has previously been associated with an intermediate form of LTP, LTP2. However, inhibition of the increased HDAC activity 12 h post-LTP by TSA had no effect on the persistence of LTP, nor did it make the LTP more susceptible to disruption by LTP induction at a competing input onto the same set of cells. An additional important finding from this work was that HDAC activity and protein expression was regulated in the contralateral non-tetanised hemisphere. This led to the hypothesis that increased HDAC activity may create an environment in which persistent LTP could not be induced. We found, however, that despite heightened HDAC activity, LTP was able to be induced and persisted as normal. Our findings do not support the hypothesis that LTP persistence is supported by HDAC1 and HDAC2 activity. However, we have identified an intermediate enhancement of plasticity over the first week after induction. This leads to the suggestion that HDAC1 and HDAC2 may regulate genes involved in the early stages of learning and memory formation but not the very long-term consolidation process. Further, interhemispheric communication may occur after LTP induction, though the mechanisms of action remain unclear. We can conclude that temporally and spatially widespread mechanisms underlie the induction and maintenance of LTP and though we are yet to elucidate the maintenance mechanisms for LTP, we are beginning to tease apart the intricate mechanisms involved over 24 h post-LTP induction.