Epigenetic regulation of microglial phosphatidylinositol 3‐kinase pathway involved in long‐term potentiation and synaptic plasticity in rats

Abstract

Microglia are the main form of immune defense in the central nervous system. Microglia express phosphatidylinositol 3‐kinase (PI3K), which has been shown to play a significant role in synaptic plasticity in neurons and inflammation via microglia. This study shows that microglial PI3K is regulated epigenetically through histone modifications and posttranslationally through sumoylation and is involved in long‐term potentiation (LTP) by modulating the expression of brain‐derived neurotrophic factor (BDNF), which has been shown to be involved in neuronal synaptic plasticity. Sodium butyrate, a histone deacetylase inhibitor, upregulates PI3K expression, the phosphorylation of its downstream effectors, AKT and cAMP response element‐binding protein (CREB), and the expression of BDNF in microglia, suggesting that BDNF secretion is regulated in microglia via epigenetic regulation of PI3K. Further, knockdown of SUMO1 in BV2 microglia results in a decrease in the expression of PI3K, the phosphorylation of AKT and CREB, as well as the expression of BDNF. These results suggest that microglial PI3K is epigenetically regulated by histone modifications and posttranslationally modified by sumoylation, leading to altered expression of BDNF. Whole‐cell voltage‐clamp showed the involvement of microglia in neuronal LTP, as selective ablation or disruption of microglia with clodronate in rat hippocampal slices abolished LTP. However, LTP was rescued when the same hippocampal slices were treated with active PI3K or BDNF, indicating that microglial PI3K/AKT signaling contributes to LTP and synaptic plasticity. Understanding the mechanisms by which microglial PI3K influences synapses provides insights into the ways it can modulate synaptic transmission and plasticity in learning and memory.

miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A

“…Pathway analysis further revealed that several miRNAs including miR-29b-3p, miR-21-5p, miR-19b-3p, miR-101-3p, and miR-30c-5p, were found to be upregulated in activated microglia. These miRNAs target different members of the PI3K/Akt (protein kinase B) pathway, which is involved in the NF-κB-dependent inflammatory response of activated microglia (Saponaro et al, 2012) and long-term potentiation (LTP) through BDNF (Saw et al, 2020).…”

“…Many signaling pathways are important for microglia-mediated synaptic maintenance in the healthy and pathological brain. Of note, a recent study reported the significant contribution of microglial brain-derived neurotrophic factor (BDNF) towards learning-dependent synapse formation (Parkhurst et al, 2013;Saw et al, 2020). However, the molecular and epigenetic mechanisms underlying microglia-mediated maintenance of neuronal synapses under health and diseases remain unclear.…”

Epigenetic Regulation of the Hippocampus, with Special Reference to Radiation Exposure

“…They play key roles in the housekeeping activities of the brain, providing protection and support and maintaining homeostasis in the CNS. While once thought to only play minor supporting roles in the housekeeping of the brain, they have now been shown to be crucial in regulating synaptic plasticity, transmission and memory formation [ 119 , 120 , 121 ]. In the hippocampus, glial cells have long been shown to play integral roles in the regulation of neuronal connections and synaptic transmission [ 119 , 122 , 123 , 124 ], and this finding has not changed over time but has become more and more evident.…”

“…Microglia have been shown to be epigenetically regulated by histone modifications and also post-translationally regulated by sumoylation [ 120 ]. Inhibition HDACs brought about an enrichment H3K9ac in the promoter region of microglial phosphatidylinositol 3-kinase (PI3K) [ 120 ], a key player in neuronal long-term potentiation (LTP) [ 144 ].…”

“…Microglia have been shown to be epigenetically regulated by histone modifications and also post-translationally regulated by sumoylation [ 120 ]. Inhibition HDACs brought about an enrichment H3K9ac in the promoter region of microglial phosphatidylinositol 3-kinase (PI3K) [ 120 ], a key player in neuronal long-term potentiation (LTP) [ 144 ]. The effects of HDAC inhibition on the PI3K/Protein kinase B (AKT) pathway ultimately affect the expression of microglial BDNF, which has been shown to act on neurons and alter synapse formation and transmission [ 145 ].…”