Reduced synaptic-function explains neuronal atrophy in major depressive disorder
medwireNews: Patients with major depressive disorder (MDD) have lower expression of synaptic-function-related genes in the dorsolateral prefrontal cortex (dIPFC) than their counterparts without the condition, indicate findings from a gene profiling study.
The findings could help explain previous study results that show reduced brain volume and smaller size and density of neurons in the dIPFCs of MDD patients during imaging and postmortem examination, say the researchers.
"Decreased expression of these genes in response to chronic stress exposure also suggests an etiological relationship to MDD, which is often associated with severe life stress and trauma," write Ronald Duman (Yale University, New Haven, Connecticut, USA) and colleagues in Nature Medicine.
Further, the team observed that a transcriptional repressor, GATA1, was significantly increased in MDD patients compared with healthy individuals, and that when expressed in pre PFC neurons, causes loss of dendritic spines and dendrites, and produces depressive behavior in rats.
"GATA1 is a member of a zinc finger family of transcription factors that is evolutionarily conserved and has key roles in embryonic development," remark the researchers.
Duman and co-workers used data from a previous gene expression study involving MDD patients and matched controls to reveal a set of downregulated genes in the former group, including those related to synaptic function - calmodulin 2, synapsin I and III, Rab3A/4B, and neurogranin.
Indeed, further in situ hybridization analysis of five genes confirmed by polymerase chain reaction analysis - CALM2, SYN1, RAB3A, RAB4B, and TUBB4 - showed lower expression in the gray matter of the dIPFC in MDD patients.
Chronic unpredictable stress has been shown to decrease expression of these genes in animal models, note the authors.
The results of microarray analysis showed significantly increased messenger RNA expression of one particular transcription factor, GATA1, in patients with MDD, regardless of medication status, age at first episode, number of episodes, or suicide.
Viral expression of GATA1 significantly decreased the number of dendrite intersections, and after infusing vectors into the PFC of rats, induced depressive-like behaviors including increased time spent immobile and an increased number of escape failures while under the chronic stress of avoidance testing.
Taken together, the results suggest that "approaches that block or reverse neuronal atrophy in the PFC could be effective antidepressant treatments" in patients with MDD, conclude Duman et al.
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By Sarah Guy, medwireNews Reporter