Epigenetic regulation by G9a/ GLP complex ameliorates amyloid‐beta 1‐42 induced deficits in long‐term plasticity and synaptic tagging/capture in hippocampal pyramidal neurons

Summary Altered epigenetic mechanisms are implicated in the cognitive decline associated with neurodegenerative diseases such as in Alzheimer's disease ( AD ). AD is the most prevalent form of dementia worldwide; amyloid plaques and neurofibrillary tangles are the histopathological hallmarks of AD . We have recently reported that the inhibition of G9a/ GLP complex promotes long‐term potentiation ( LTP ) and its associative mechanisms such as synaptic tagging and capture ( STC ). However, the role of this complex in plasticity impairments remains elusive. Here, we investigated the involvement of G9a/ GLP complex in alleviating the effects of soluble Amyloid‐β 1‐42 oligomers ( oA β) on neuronal plasticity and associativity in the CA 1 region of acute hippocampal slices from 5‐ to 7‐week‐old male Wistar rats. Our findings demonstrate that the regulation of G9a/ GLP complex by inhibiting its catalytic activity reverses the amyloid‐β oligomer‐induced deficits in late‐ LTP and STC . This is achieved by releasing the transcription repression of the brain‐derived neurotrophic factor ( Bdnf ) gene. The catalytic inhibition of G9a/ GLP complex leads to the upregulation of Bdnf expression in the slices treated with oA β. This further ensures the availability of BDNF that subsequently binds its receptor tyrosine kinase B (TrkB) and maintains the late‐ LTP . Furthermore, the capture of BDNF by weakly activated synapses re‐establishes STC . Our findings regarding the reinstatement of functional plasticity and associativity in AD ‐like conditions provide the first evidence for the role of G9a/ GLP complex in AD . We propose G9a/ GLP complex as the possible target for preventing oA β‐induced plasticity deficits in hippocampal neurons.