While there are a lot of reasons to anxious these days, thankfully our neurons are using epigenetics to respond and adapt to the barrage of new information in our environment. In fact, DNA cytosine hydroxymethylation (5hmC) might be necessary to keep cognition in check, and a new research suggests that one of the enzymes that converts 5mC to 5hmC has an important role in anxiety-related behaviors.
A study from the lab of Joana Marques (University of Porto, Portugal) utilized Tet3 conditional knockout mice (cKO) to examine the enzyme’s role in mature neurons. The talented team bred the animals so that the Tet3 gene would be deactivated in the mature neurons of the forebrain after they were injected with tamoxifen, and found that:
- Tet3 proteins in control animals strongly colocalize with neuronal markers (NeuN), weakly colocalize with oligodendrocytes markers (CNPase), and don’t colocalize at all with markers of astrocytes (GFAP) as measured by immunofluorescence in the hippocampus and cortex
- cKO mice express less Tet3 mRNA and protein in their prefrontal cortex, amygdala and hippocampus, but have no changes in global 5hmC levels, as measured by ELISA, compared to wildtype controls
- Tet3 knockout mice have increased anxiety-like behaviors, including spending less time in the center of an open field test, and taking longer to enter the open arms of an elevated plus maze when compared to control animals
- Conversely, Tet3 knockout has no effect on behaviors related to depression, including time spent immobile in the forced swim and tail suspension tasks
- cKO animals also have higher levels of the stress hormone corticosterone, which is a sign of overactivity in the hypothalamus-pituitary-adrenal axis
- Although cKO mice perform as well as their WT counterparts in object recognition and short-term memory tasks, they are less likely to use spatial information, which uses the hippocampus, to find a hidden platform in the Morris Water Maze test
- The expression of 143 transcripts is altered in the ventral hippocampus of cKO mice, as measured by RNA-seq, including genes related to glucocorticoid signalling, FOXA1 transcription factor network, and activity-induced genes involved in synaptic plasticity
- Tet3 deletion has no effect on the length or complexity of the dendrites of pyramidal neurons; however, cKO mice have more mature dendritic spines in the ventral hippocampus compared to controls
While we know that other Tet enzymes might defend against cognitive malfunctions in mice, this study is the first to show that Tet3 shields against anxiety by maintaining neuronal plasticity.
Let your guard down and check out the original article in Molecular Psychiatry, February 2020.