Repetitive Transcranial Magnetic Stimulation Reduces Depressive-like Behaviors, Modifies Dendritic Plasticity, and Generates Global Epigenetic Changes in the Frontal Cortex and Hippocampus in a Rodent Model of Chronic Stress

Abstract

Depression is the most common affective disorder worldwide, accounting for 4.4% of the global population, a figure that could increase in the coming decades. In depression, there exists a reduction in the availability of dendritic spines in the frontal cortex (FC) and hippocampus (Hp). In addition, histone modification and DNA methylation are also dysregulated epigenetic mechanisms in depression. Repetitive transcranial magnetic stimulation (rTMS) is a technique that is used to treat depression. However, the epigenetic mechanisms of its therapeutic effect are still not known. Therefore, in this study, we evaluated the antidepressant effect of 5 Hz rTMS and examined its effect on dendritic remodeling, immunoreactivity of synapse proteins, histone modification, and DNA methylation in the FC and Hp in a model of chronic mild stress. Our data indicated that stress generated depressive-like behaviors and that rTMS reverses this effect, romotes the formation of dendritic spines, and favors the presynaptic connection in the FC and DG (dentate gyrus), in addition to increasing histone H3 trimethylation and DNA methylation. These results suggest that the antidepressant effect of rTMS is associated with dendritic remodeling, which is probably regulated by epigenetic mechanisms. These data are a first approximation of the impact of rTMS at the epigenetic level in the context of depression. Therefore, it is necessary to analyze in future studies as to which genes are regulated by these mechanisms, and how they are associated with the neuroplastic modifications promoted by rTMS.

New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity

“…On the other hand, epigenetics is a stable and long-lasting event that is associated with sustained antidepressant efficacy. A number of publications have investigated depression based on epigenetics [ 86 , 87 ]. From this perspective, could epigenetics serve as a bridge between sustained antidepressant efficacy and neurexins that modulate synaptic plasticity?…”

Epigenome Defines Aberrant Brain Laterality in Major Mental Illnesses

“…As rTMS is an effective therapy in multiple neuropsychiatric illnesses, including Alzheimer’s disease (AD), an animal study uncovered that rTMS can improve neuronal activity by increasing cFos expression, decrease astrocyte and microglia activation, and reduce Aβ deposits in high-fat diet-induced mice models of AD [ 142 ]. Additionally, in chronic unpredictable stress-induced depression in mice, rTMS could improve depression and dendritic remodeling associated with an increase in histone H3 trimethylation (H3K9me3, a repressor epigenetic mark) in the frontal cortex along with DNA methylation changes in the hippocampus, both globally and in mature neurons [ 143 ]. In humans, rTMS therapy could alter the DNA methylation of the COMT gene in the blood cells of patients with PTSD, where reduced DNA methylation over time was associated with a better response [ 144 ].…”