Tet2negatively regulates memory fidelity

Abstract

Despite being fully differentiated, DNA methylation is dynamically regulated in post-mitotic glutamatergic neurons in the CA1 of the hippocampus through competing active DNA methylation and de-methylation, a process that regulates neuronal plasticity. Active DNA methylation after learning is necessary for long-term memory formation, and active DNA de-methylation by the TET enzymes has been implicated as a counter-regulator of that biochemical process. We demonstrate that Tet2 functions in the CA1 as a negative regulator of long-term memory, whereby its knockdown across the CA1 or haploinsufficiency in glutamatergic neurons enhances the fidelity of hippocampal-dependent spatial and associative memory. Loci of altered DNA methylation were then determined using whole genome bisulfite sequencing from glutamatergic Tet2 haploinsufficient CA1 tissue, which revealed hypermethylation in the promoters of genes known to be transcriptionally regulated after experiential learning. This study demonstrates a link between Tet2 activity at genes important for memory formation in CA1 glutamatergic neurons and memory fidelity.

Tet1Isoforms Differentially Regulate Gene Expression, Synaptic Transmission, and Memory in the Mammalian Brain

“…Knock-down (KD) of Tet3 alters synaptic transmission, and conditional knock-out (KO) of the gene impairs spatial memory, indicating that its necessary for cognition ( Yu et al, 2015 ; Antunes et al, 2020 ). Tet2 is also abundantly expressed in the brain and its disruption is associated with enhanced spatial memory, suggesting it may function as a negative regulator of neuroplasticity ( Zengeler et al, 2019 ). Tet1 , despite much lower expression, has been the most studied Tet family member in the nervous system, implicated in the regulation of activity-dependent gene expression, synaptic transmission, and cognition ( Alaghband et al, 2016 ).…”