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Tet1 Overexpression leads to Anxiety-like Behavior and Enhanced Fear Memories in Mice
Tet1 is well known initiatior of DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine in CpG-rich regions of the brain. There have been studies using Tet1-KO mice about adult neurogenesis, cognition and memory extinction, it is still unclear whether Tet1 overexpression is beneficial for CNS networks. Thus in this study, Tet1 overexpression TG mice were developed and behavioral phenotypes were analyzed with related gene studies. Most of all, they showed anxiety-like behaviors and improved memories with increased immature neurons in the hippocampal dentate gyrus. Hence, they showed increased immediate-early gene levels (c-Fos, Arc, Egr-1, and BDNF), activation of intracellular calcium signaling (CamKII, ERK, and CREB) and changes in the expression of GABA receptor subunits (GABRA2, and GABRA4) in several brain regions. By overexpressing Tet1 in NB41A3 cells, effect of Tet1 overexpression on intracellular calcium levels with higher Egr-1 promoter activity was evaluated. These findings suggests Tet1 overexpression affects excitatory synaptic networks via activating NMDAR-dependent calcium signaling which leads to dysregulation of inhibitory synaptic networks. Also, it implies chronic and excessive activation of intraneuronal calcium signaling by Tet1 leads to behavioral differences in mice. Additionally, it suggests Tet1 overexpression in the PFC, hippocampus, and amygdala contributes as both beneficial and harmful for neural networks in differing aspects.
