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Short Answered Question Papers > Decreased expression of Synapse-related Genes and Loss of Synapses in Major Depressive Disorder > Flashcards

Decreased expression of Synapse-related Genes and Loss of Synapses in Major Depressive Disorder Flashcards

1
Q

MDD

A

Major Depressive Disorder

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2
Q

What is the aim of this study?

A

To show evidence for reduction in expression of synaptic function related genes in post mortem and rat model studies.

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3
Q

What are the effects of inhibition of synaptic function related genes?

A
  • Reduction in brain volume

- Decrease in the size and density of neurons

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4
Q

What brain area is the most affected?

A

The dlPFC (dorso-lateral Prefrontal Cortex)

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5
Q

What genetic identification techniques are used to monitor the rate of expression of synaptic related genes?

A
  • Microarray gene profiling

- Electron microscopic stereology

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6
Q

How many individuals does MDD affect in the population?

A

17 percent of US population

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7
Q

Name the symptoms of MDD

A
  • Cognitive impairment

- Loss of memory

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8
Q

What are the findings from rat model studies?

A
  • Reduction in spine number

- Reduction/impairment of neuronal function (LTD)

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9
Q

What are the findings from post mortem studies?

A

Morphometric changes in prefrontal cortex of MDD subjects:

- Reduction in neuronal body size

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10
Q

What is the other name of the dlPFC?

A

Brodmann area 9

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11
Q

What are the specific synaptic categories and their correspondent affected genes?

A
  • Regulation of synaptic strength LTP (NRGN)
  • Regulation of synaptic vesicle release (CAM2, SYN1/3, RAB3A4, AMPH SYNGR3)
  • Dendritic spine formation (RAB4B)
  • Axonal outgrowth and Regeneration (TUBB2/4)
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12
Q

What gene codes for Synaptogyrin 3?

A

SYNGR3

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13
Q

What gene codes for synapsins 1/3?

A

SYN1 and SYN3

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14
Q

What gene codes for Tubulins 2/4?

A

TUBB2 and TUBB4

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15
Q

What do the genes RAB3A RAB4B code for?

A

Ras related GTP-binding protein 3A and 4B

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16
Q

What was discovered with the PCR analysis?

A

A reduction in 5 of the 10 genes

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17
Q

What was shown with the in situ hybridization?

A

Enriched expression in gray matter of dlPFC

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18
Q

What did the quantitative analysis of the results show?

A

The levels of expression these five genes were significantly decreased in MDD subjects compared to control

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19
Q

What does CUS stand for?

A

Chronic unpredictable Stress

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20
Q

What were the findings of the CUS study in rodents?

A

That expression of Synapsin I, Calmodulin II, RAB3A, and RAB4B, was decreased in the prefrontal cortex.
- Suggesting that the reduced levels of these synapse related genes in MDD result from Chronic stress exposure = depressive behaviour.

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21
Q

The results from the rodent study prove that there is reduction in synaptic density of neurons in the dlPFC.

A

False there is no evidence for this

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22
Q

What the five genes under-expressed in MDD human subjects?

A
  • CALM2 (Calmodulin 2)
  • RAB3A (Ras rekated GTP-binding protein 3A)
  • RAB4B 9Ras related GTP-binding protein 4B)
  • TUBB4 (Tubulin 4)
  • TUBB2 (Tubulin 2)
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23
Q

What does shRNA stand for and what was it used for in the rodent study?

A

Small hairpin RNA (ribose nucleic acid)

Used to examine the influence of GATA1 on chronic stress derived depressive behaviour.

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24
Q

What was shown by the examination of dendrite morphology with MAP2 immunohistochemistry?

A

Decreased staining of dendritic processes in dlPFC layers 3-5 of MDD subjects relative to controls, confirmed by AMP2 immunoblotting the dlPFC micro-punches.

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25
What was observed with the electron microscopic stereological analysis?
Decrease in spine synapse number in MDD subjects compared to controls
26
What did the co-factor analysis reveal?
- No significant effects of medication status - Age of first episode - Suicide But the sample was small.
27
What was found in the examination of TF binding motifs in the promoter regions of the decreased synapse-related genes?
3266 upstream regulatory elements for 218 transcription factors.
28
What method was used in the examination of TF binding motifs?
TRANSFAC scoring matrix
29
How many TF binding sites are found upstream to the regulatory domain of the MDD and CUS=altered genes?
12
30
What method was used to identify the expression GATA1 TF?
Microarray data analyses was used to identify the over-expression of the GATA1 TF in MDD and CUS
31
Is the GATA1 TF solely found in humans?
No it can also be found in rodents
32
What are other TFs that were identified and are they relevant?
- KID31.0 - GKLF And they were either not significant altered or not included in the microarray gene set.
33
What are the names of the GATA1 isoforms and their relevance to the study?
- GATA 2, 3, and 4 isoforms were not significantly expressed compared to controls
34
What was found in the CUS rodent model of depression study?
Increased GATA1 expression in the PFC can be reverted by chronic administration of Fluoxetine
35
Why is it that anti-depressant medication can normalize GATA1 expression in rodents but not in MDD?
Possibly due to - small number of the medicated and un-medicated sub-groups - Treatment resistance - Heterogeneity of the subjects
36
How was the binding activity of the GATA1 TF to the promoter of the synapse of synaptic function related genes confirmed?
chromatin immunoprecipitation with a GATA1 antibody followed by PCR for the GATA1 binding region of each gene.
37
What does chIP stand for?
chromatin immunoprecipitation
38
What was found in the analysis of neuronal cultures?
The possibility that elevated GATA1 underlies decreased expression of the synapse-related genes and the atrophy of dendritic processes.
39
What is the importance of RAB4B?
This class of small GTP-binding protein is required foe endosomal recycling critical for the maintenance of spine size. Its rate of expression was the most reduced/
40
How was the decrease in RAB4B shown?
GFP tagged rAAV-GATA1 vector inserted in neuronal cell culture significantly decreased the expression of RAB4B
41
How can we be sure that the decrease in RAB4B is due to the viral GATA1?
FOG1, GATA1 positively regulated cofactor, was significantly increases by viral expression of GATA1.
42
How was dendrite morphology analysed?
Neurons were fixed with anti-GFP and MAP2 antibodies.
43
What was the effect of GATA1 on the dendritic arbor?
Viral expression of GATA1 decreased the complexity of dendritic arbor, the number of synpases and the intensity of MAP2 staining
44
What was demonstrated by the Sholl analysis?
Viral expression of GATA1 significantly decreased the numbe rof dendrite intersections, indicating decreased complexity of dendritic arbor.
45
What does GFP stand for?
green fluorescent protein
46
What does MAP2 stand for?
microtubule associated protein
47
What are the components of the viral vectors infused into the rodent PFC in the GATA1 expression effect on behaviour?
ITRs (inverted terminal repeats) Cytomegalovirus promotr human growth Hormone PolyA
48
What effect did the viral infusion of GATA1 have on the rodent behaviour?
GATA1 produced depressive like behaviours in two rodent models; - Forced swim test - Learned helplessness model
49
Describe the effect the viral infusion of GATA1 have on Forced swim test?
- Increased the time spent immobile
50
Describe the effect the viral infusion of GATA1 have on Learned helplessness model?
- Increased the number of escape failures during the initial block of active avoidance testing
51
Are the viral GATA1 effects in Forced swim test reversed by anti depressant medication?
Imipramine did not reverse the effects of viral GATA1 as expected.
52
How was the influence of GATA1 on depressive behaviour examined?
With a viral knock down strategy using a small hairpin RNA targeted to GATA.
53
What is the effected of the shRNA viral GATA1 on GATA1 mRNA and how was that verified?
It effectively decreases GATA1 mRNA confirmed in cultured cells and rat PFC.
54
What does the CUS paradigm induce?
Anhedonia measured by preference of a sweetened solution
55
What was the symptomatic effect of viral GATA1 shRNA in the CUS paradigm?
It blocked the anhedonia, rats went for the sweetened solution
56
Which synapse related genes are located pre-synaptically?
- SYN1 - RAB3A - CALM2 and - PUBB 2/4
57
Which synapse related genes are located post-synaptically?
- RAB4B
58
What are the two main conclusion of this study?
1. Identification of credible molecular and cellular mechanisms that can cause a reduction i synapse number, dendritic complexity = neuronal atrophy + decreased cortical volume in MDD patients. 2. Approaches that block or reverse neuronal atrophy of PFC could be effective anti-depressants.
59
What conclusion from another study support the findings of Kang et al.?
The rapid antidepressant actions of NMDA receptor blockade are associated with increased spine number and function, and increased synaptogenesis in the PFC.
60
How was the neuron culture generated?
Embryonic brain were prepared from fetal SD rats at 18 day gestation and mechanically triturated.
61
What is the other name for viral GATA1?
rAAv-GATA1
62
What did Sholl analysis investigate?
Dendritic Branching

Short Answered Question Papers (2 decks)

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