article Flashcards
How much people are affected by MDD
Major depressive disorder (MDD) affects approximately 17 percent of the population,
What is predicted in the year 2023 for MDD
it is predicted to be the number two cause of illness worldwide by the year 20203 .
Symptoms of MDD and what does it implicate
- cognitive impairment
- loss of memory,
implicating synaptic dysfunction in the pathophysiology of MDD.
What are the 3 molecular and cellular changes found in mDD patients and how were they discovered and what does all these studies demonstrate
- a reduction of dendritic spine number and function of neurons in PFC in animal models of depression
- Postmortem studies also report morphometric changes in PFC of MDD subjects, including a reduction in neuronal body size
- This is also consistent with brain imaging studies reporting a reduction in the volume of PFC subregions in MDD subjects
Together, these studies suggest a loss of spine number and dendritic arbor although there is no direct evidence demonstrating this type of neuronal atrophy in the brains of MDD subjects
How were the mechanisms of neuronal atrophy and reduced volume of PFC studied in this study
To gain insight into the mechanisms that underlie neuronal atrophy and reduced volume of PFC, we have re-analyzed the data from a prior microarray gene expression study that we conducted of the dlPFC (Brodmann area 9) of MDD subjects and matched controls
What did this study looking at mechanisms of neuronal atrophy and reduced volume of PFC find
- We classified the microarray data with a 5% FDR11and found that about 30% of the downregulated genes in the MDD group could be related to some aspect of synaptic function.
- A more extended range (20% cutoff) identified an additional subset of down-regulated synaptic function-related genes in dlPFC of MDD brains
What synaptic categories were found in this study
- Regulation of synaptic vesicles
- [calmodulin 2, synapsins I and III, Rab3A, amphiphysin, and synaptogyrin 3] - Regulation of synaptic strength [neurogranin]
- Dendritic spine formation [Rab4B]18, and axonal outgrowth and regeneration [tubulins]
What gene alterations have genome-wide expression studies found of MDD
gene alterations of similar functional categories, including 1. cytoarchitecture
- vesicular transport,
- synaptic transmission,
- some of the same synapse-related genes or isoforms of the genes identified here (e.g., subtypes of amphiphysin, synaptogyrin, synapsin, and the Ras superfamily
What did PCR analysis show
PCR analysis demonstrated significant decreases for 5 of the 10 genes, and trends for all but one (amphiphysin) of the remaining genes in the dlPFC of MDD subjects (Table 1).
What did In situ hybridization analysis confirm
1In situ hybridization analysis of the five confirmed genes demonstrates enriched expression in gray matter of dlPFC with a laminar distribution in the middle (synapsin I) or middle and deep layers (calmodulin 2, Rab3A, Rab4B and β-tubulin 4) of dlPFC.
What did Quantitative analysis confirm
Quantitative analysis confirms that levels of these five genes are significantly decreased in MDD subjects compared to controls
What does CUS stand for
chronic unpredictable stress
What did Studies in rodents with chronic unpredictable stress (CUS) show?
Studies in rodents demonstrate that chronic unpredictable stress (CUS), considered one of the most valid rodent models of depression, decreases the expression of synapsin I, calmodulin 2, Rab3A, and Rab4B, but not beta-tubulin 4, in the PFC (Supplementary Fig. 1), suggesting that the decreased levels of these synapse-related genes in MDD result from chronic stress exposure that could contribute to depressive behaviors.
How was dendritic morphology examined
microtubule-associated protein 2 (MAP2) immunohistochemistry
What did the examination of dendritic morphology show and how was it confirmed
evealed decreased staining of dendritic processes in dlPFC layers III through V of MDD subjects relative to controls, which was confirmed by MAP2 immunoblotting of dlPFC micro-punches
What did electron microscopic stereological analysis show
Using electron microscopic stereological analysis, a marked decrease in spine synapse number was observed in MDD subjects compared to controls (Fig. 1h).
What did Co-factor analysis reveale
no significant effects of medication status, age of first episode age of first episode (<40 vs. ≥40 years old), or suicide on synapse number
What did Examination of the transcription factor binding motifs show
Examination of the transcription factor binding motifs in the promoter regions of the decreased synapse-related genes identified 3,266 upstream regulatory elements for 218 transcription factors (TRANSFAC scoring matrix,
12 transcription factor binding sites are localised to where?
Twelve transcription factor-binding sites are localized to the upstream regulatory domain of all of the MDD and CUS-altered synapse-related genes (Fig. 2a).
The rat homologues of these synapse-related genes included what
The rat homologues of these synapse-related genes include eight of the twelve transcription factor regulatory elements .
What did Analysis of the microarray data reveal
Analysis of the microarray data revealed that one of these transcription factors GATA1 is significantly increased in MDD patients
which transcriptions factors were either not significantly changed in MDD
Other transcriptions factors were either not significantly changed in MDD (GKLF and KID31.0- and 1.1-fold, respectively) or were not included in the microarray gene set.
Levels of what GATA isoforms were not altered in MDD compared to controls
Levels of the related GATA-2, 3, and 4 isoforms were not significantly altered in MDD compared to controls.
Co-factor analysis revealed what in GATA1 expression
Co-factor analysis revealed no effect of medication status on GATA1 expression, and no significant differences between all MDD subjects and groups categorized by age of first episode, number of episodes, and suicide, although the number of subjects per subgroup was small