Dnmt1/3a deletion in prefrontal cortical neurons reduces palatable food intake

DNA methylation is an important regulatory mechanism in the control of neuronal function. Both during development and following exposure to salient stimuli, plasticity in the methylation of cytosine residues leads to a change in neuron excitability that subsequently sculpts animal behavior. However, while the response of DNA methyltransferase enzymes in adult neurons to stimuli such as drugs of abuse have been described, less is known about how these enzymes regulate methylation at specific loci to change an animal's inclination to ingest natural rewards. Specifically, we do not understand how changes in methylation within important brain areas known to regulate palatable food intake can affect ingestion, and detailed investigation of the neurophysiological and genomic effects of perturbing methyltransferase function has not been pursued. By deleting DNA methyltransferase 1 and 3a in the mouse prefrontal cortex, we observed the requirement for these enzymes in the regulation of nutrient rich food consumption in the absence of any effect on the intake of low fat and low sugar chow. We also determined that the deletion profoundly affected neuron excitability within pyramidal cells resident in superficial layers II/III of the cortex but had little effect in deep layer V neurons. Finally, reduced representation bisulfite sequencing revealed both hypo and hypermethylation in response to methyltransferase deletion, an effect that was observed in binding sites for retinoic acid receptor beta (RARß) located within regulatory regions of genes known to affect neuronal function. Together, our data suggest that alterations in the actions of RARß could shift neuronal activity to reduce palatable food intake. Overall design: C57BL/6 and, DNMT1 and DNMT3a floxed mice were injected with Synapsin promoter-driven Cre-GFP AAV. Methylomes of medial prefrontal cortex pyramidal neurons with and without DNMT1 and DNMT3a were profiled.