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Focus on Synaptic Loss in Depression

6 September 2012.In a study, published online August 12 in Nature Medicine, researchers report a lower expression of synapse-related genes and a loss of synapses in postmortem prefrontal cortex tissue from subjects with major depressive disorder (MDD). Increased levels of GATA1 may be a mechanism underlying these synaptic alterations in MDD, as viral overexpression of this transcription factor by Ronald Duman and colleagues at Yale University, New Haven, Connecticut, induced similar gene changes and decreased the complexity and number of dendritic spines in cortical cultures, and produced several depression-like behaviors in rats. Symptoms of MDD include cognitive impairments and memory loss, suggesting a reduction of synapses as found in other illnesses like Alzheimer’s disease with similar symptoms (Levens and Gotlib, 2009). In fact, decreased dendritic spine number and altered neuronal functioning has been reported in animal models of MDD (Radley et al., 2006; Liu et al., 2008) and postmortem studies have found smaller neuronal size and smaller prefrontal cortex volume (Rajkowska et al., 1999; Drevets, 2000). However, despite this evidence suggesting loss, a direct measurement of synapses in MDD had been lacking.

The state of the synapse
In the current study, first author Hyo Jung Kang and colleagues used multiple approaches to examine synapses in MDD. First, the researchers analyzed previously published microarray data from the dorsolateral prefrontal cortex (DLPFC) of subjects with MDD and matched controls (Kang et al., 2007), finding that a third of the genes that were decreased in MDD were related to synapse functioning. Decreased expression of five of these genes—CALM2, SYN1, RAB3A, RAB4B, and TUBB4—replicated using both PCR and in situ hybridization. Levels of the first four genes were also lower in a rodent model of depression—chronic unpredictable stress—suggesting that the lower expression of these genes in MDD may be a consequence of exposure to stress.

To more directly examine synapse density, the authors then used electron microscopic stereological analysis, finding a greater than 50 percent reduction in the number of synapses per volume of tissue in MDD. In agreement with these results, there was reduced staining on MAP2-positive dendritic processes in MDD. Thus, the reduction in synapse-related genes likely reflects a loss of synapses.

GATA1: upstream of synapse loss?
Microarray analysis also demonstrated that mRNA levels of the transcription factor GATA1 are increased in the DLPFC of subjects with MDD. Using chromatin immunoprecipitation, the researchers showed that GAT1 binds to the promoter region of all five of the differentially expressed synaptic genes. In addition, GAT1 was increased after stress exposure.

To investigate the transcription factor’s role in the synapse alterations of MDD, researchers virally overexpressed GATA1 in primary neuronal cultures. They then examined the levels of RABB4 (chosen because it showed the largest decrease in MDD) after GATA1 overexpression. GATA1 overexpression lowered the levels of RABB4 and also decreased the complexity of the dendritic arbor, the number of spines, the amount of MAP2 staining. Overexpression in rat prefrontal cortex also produced depressive-like behaviors in rats administered the forced swim test and learned helplessness model, but did not affect locomotion. Rats subjected to chronic stress exhibited increased levels of GATA1, and viral-mediated knockdown of GATA1 in these animals attenuated another depression-like behavior, anhedonia, as measured using the sucrose preference test.

In summary, Kang and colleagues have shown that MDD is characterized by decreased expression of synaptic genes and a reduction in the number of synapses per volume of tissue in the DLPFC. Their data also suggest that overexpression of the transcription factor GATA1 may be a plausible mechanism underlying these synaptic changes in MDD, and that pharmacological approaches that block or reverse these alterations may be of therapeutic value.—Allison A. Curley.

Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, Lepack A, Majik MS, Jeong LK, Banasr M, Son H, Duman RS. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nature Medicine. Published online 12 August 2012. Abstract

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