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  • br Memories can last a

    2021-10-09


    Memories can last a lifetime, long after the transient events have passed. The fact that information stored in the MK2 Inhibitor IV australia can outlast the environmental trigger implies that enduring cellular changes in the central nervous system underlie memory. Epigenetic modifications of DNA and chromatin structure have been considered as one of the critical molecular events that lead to the formation of memory engrams. The study of epigenetics in learning and memory is burgeoning; accumulating evidence illustrates that activity-dependent epigenetic modulation is indispensable for memory and synaptic plasticity (, ). Activity-dependent synaptic plasticity – namely long-term potentiation (LTP) and long-term depression (LTD) – is considered as the cellular correlate of memory (, , ). Both long-lasting LTP and LTD require tight regulation of protein synthesis and/or gene transcription (, , , ). Different phases of LTP and LTD vary in terms of persistence, signalling mechanisms and protein synthesis dependency. For example, the early phase of LTP, commonly referred to as early-LTP, relies on the modification of the existing proteins without the need for protein synthesis. Late-LTP, on the other hand, engages the transcription and translation machinery to generate plasticity-related products (PRPs) that maintain the changes in synaptic efficacy. While early-LTP wanes within one to three hours, late-LTP sustains for a longer term. These activity-dependent forms of synaptic plasticity have been demonstrated to be regulated by a range of factors including, but not limited to, the pattern and history of activity, neuromodulation, transcription, translation and epigenetics. Studies in the past two decades have made clear the importance of epigenetic regulation in learning and memory (, ). Once neglected, the role of histone lysine methylation in cognition is garnering support (, , ). Among the many regulators of histone methylation, the histone lysine methyltransferase (HKMT) complex G9a/GLP has received considerable attention, in part due to the fact that GLP deletion/mutation causes Kleefstra syndrome, a genetic condition characterized by intellectual disability (, ). G9a/EHMT2 and GLP/EHMT1 function as a heteromeric complex () and are key enzymes for mono- and di-methylation of lysine 9 of histone H3 (H3K9me1 and H3K9me2) in euchromatin (). The H3K9me2 mark is associated with transcriptional repression () and G9a/GLP is mainly considered as an epigenetic suppressor (). However, growing evidence suggests that G9a also acts MK2 Inhibitor IV australia as a coactivator in association with other transcription factors and co-factors (, , ). In addition to its roles in embryonic development, cell cycle regulation and immune responses, the role of G9a/GLP in the formation of long-term memory has been highlighted in recent studies (, , , ). To name a few, G9a is demonstrated to be critical for contextual fear conditioning () and contextual place preference (CPP) (, ) in rodents. Our limited understanding of the role of G9a/GLP complex in learning and memory is mostly derived from clinical observations () and behavioural studies (, ). However, we are yet to decipher the exact role of the G9a/GLP complex in the molecular mechanisms of cognition. In this review, we will be discussing the developments in our efforts to unravel the role of G9a/GLP complex in synaptic plasticity, the cellular basis of learning and memory, alongside G9a/GLP function in mediating other neuronal properties. The involvement of G9a/GLP complex in synaptic plasticity has been investigated using pharmacological as well as genetic approaches. Pharmacological inhibition of G9a/GLP complex by competitive inhibitors UNC and BIX (, ) has no effect on basal synaptic transmission in Schaffer Collateral/commissural (SC)-CA1 synapses in the hippocampus (, ). In addition, heterozygous knockout mice (), an animal model for Kleefstra syndrome, displayed no difference in basal synaptic transmission in the CA1 area of the hippocampus as compared to wild-type (WT) mice (). However, these CA1 neurons showed a decrease in miniature excitatory postsynaptic current (mEPSC) frequency, but not amplitude, which might have been a consequence of the reduction in dendritic arborization and spine density. Echoing these findings, small hairpin RNA (shRNA)-mediated knockdown of (G9a) led to a reduction in mEPSC frequency, but not amplitude, in rat primary cortical neurons in culture. knockdown also reduced synapse formation, as measured by lowered PSD-95/VGLUT juxtaposition. Interestingly, such alterations in synapse formation and function were not observed in GLP-deficient neurons. shRNA knockdown of (GLP) and pharmacological inhibition of G9a/GLP complex activity by UNC did not alter mEPSC frequency or amplitude under basal conditions. However, both G9a and GLP are needed for the tetrodotoxin-induced increase in H3K9me2 levels and homeostatic synaptic scaling up (Benevento, Iacono et al. 2016). Taken together, these results suggest that G9a/GLP complex most likely does not play a critical role in regulating vital neuronal function under basal conditions; instead, G9a and GLP may have differential roles in regulating electrophysiological properties and synaptic transmission in a brain region-, cell-type-specific and context-dependent manner.