LONG-LASTING NEUROBEHAVIORAL EFFECTS OF EARLY-LIFE STRESS: THE ROLE OF MECP2

Anxiety disorders are a group of debilitating psychiatric conditions characterized by intense and excessive worry that affect 4.8% of the population. Early-life stress (ELS) is a risk factor for the development of anxiety disorders later in life. It comprises adverse events that occur during periods of high brain plasticity early in development, including the critical period of HPA axis development that is responsible for stress responses.
ELS leaves epigenetic methylation marks in the DNA, influencing the modulation of gene expression by the epigenetic reader methyl CpG-binding protein 2 (MeCP2). MeCP2 regulates transcription by binding to methylated DNA, activating or repressing gene expression, including brain plasticity and stress-associated genes such as BDNF and NTF3.
We aim to disclose how MeCP2 mediates ELS effects in the anxiety circuitry, and its impact in later life stress responses.
Using a mouse model of maternal separation, we found that animals that undergo this ELS protocol show an increased anxiogenic response in the elevated-plus maze, not further exacerbated in response to an acute life stressor. These changes in behavior are accompanied by region-specific differences in phosphorylated-MeCP2 expression in the hippocampal CA2 region, as assessed by immunohistochemistry. Furthermore, we observed changes in expression of MeCP2 target genes by RT-PCR in hippocampal extracts. This data helps dissect the mechanisms behind MeCP2 modulation of anxiety-like behavior in response to stress later in life and its modulation by early life adversities.