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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
Q

What was observed with the electron microscopic stereological analysis?

A

Decrease in spine synapse number in MDD subjects compared to controls

26
Q

What did the co-factor analysis reveal?

A
  • No significant effects of medication status
  • Age of first episode
  • Suicide
    But the sample was small.
27
Q

What was found in the examination of TF binding motifs in the promoter regions of the decreased synapse-related genes?

A

3266 upstream regulatory elements for 218 transcription factors.

28
Q

What method was used in the examination of TF binding motifs?

A

TRANSFAC scoring matrix

29
Q

How many TF binding sites are found upstream to the regulatory domain of the MDD and CUS=altered genes?

30
Q

What method was used to identify the expression GATA1 TF?

A

Microarray data analyses was used to identify the over-expression of the GATA1 TF in MDD and CUS

31
Q

Is the GATA1 TF solely found in humans?

A

No it can also be found in rodents

32
Q

What are other TFs that were identified and are they relevant?

A
  • KID31.0
  • GKLF
    And they were either not significant altered or not included in the microarray gene set.
33
Q

What are the names of the GATA1 isoforms and their relevance to the study?

A
  • GATA 2, 3, and 4 isoforms were not significantly expressed compared to controls
34
Q

What was found in the CUS rodent model of depression study?

A

Increased GATA1 expression in the PFC can be reverted by chronic administration of Fluoxetine

35
Q

Why is it that anti-depressant medication can normalize GATA1 expression in rodents but not in MDD?

A

Possibly due to

  • small number of the medicated and un-medicated sub-groups
  • Treatment resistance
  • Heterogeneity of the subjects
36
Q

How was the binding activity of the GATA1 TF to the promoter of the synapse of synaptic function related genes confirmed?

A

chromatin immunoprecipitation with a GATA1 antibody followed by PCR for the GATA1 binding region of each gene.

37
Q

What does chIP stand for?

A

chromatin immunoprecipitation

38
Q

What was found in the analysis of neuronal cultures?

A

The possibility that elevated GATA1 underlies decreased expression of the synapse-related genes and the atrophy of dendritic processes.

39
Q

What is the importance of RAB4B?

A

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
Q

How was the decrease in RAB4B shown?

A

GFP tagged rAAV-GATA1 vector inserted in neuronal cell culture significantly decreased the expression of RAB4B

41
Q

How can we be sure that the decrease in RAB4B is due to the viral GATA1?

A

FOG1, GATA1 positively regulated cofactor, was significantly increases by viral expression of GATA1.

42
Q

How was dendrite morphology analysed?

A

Neurons were fixed with anti-GFP and MAP2 antibodies.

43
Q

What was the effect of GATA1 on the dendritic arbor?

A

Viral expression of GATA1 decreased the complexity of dendritic arbor, the number of synpases and the intensity of MAP2 staining

44
Q

What was demonstrated by the Sholl analysis?

A

Viral expression of GATA1 significantly decreased the numbe rof dendrite intersections, indicating decreased complexity of dendritic arbor.

45
Q

What does GFP stand for?

A

green fluorescent protein

46
Q

What does MAP2 stand for?

A

microtubule associated protein

47
Q

What are the components of the viral vectors infused into the rodent PFC in the GATA1 expression effect on behaviour?

A

ITRs (inverted terminal repeats)
Cytomegalovirus promotr
human growth Hormone PolyA

48
Q

What effect did the viral infusion of GATA1 have on the rodent behaviour?

A

GATA1 produced depressive like behaviours in two rodent models;

  • Forced swim test
  • Learned helplessness model
49
Q

Describe the effect the viral infusion of GATA1 have on Forced swim test?

A
  • Increased the time spent immobile
50
Q

Describe the effect the viral infusion of GATA1 have on Learned helplessness model?

A
  • Increased the number of escape failures during the initial block of active avoidance testing
51
Q

Are the viral GATA1 effects in Forced swim test reversed by anti depressant medication?

A

Imipramine did not reverse the effects of viral GATA1 as expected.

52
Q

How was the influence of GATA1 on depressive behaviour examined?

A

With a viral knock down strategy using a small hairpin RNA targeted to GATA.

53
Q

What is the effected of the shRNA viral GATA1 on GATA1 mRNA and how was that verified?

A

It effectively decreases GATA1 mRNA confirmed in cultured cells and rat PFC.

54
Q

What does the CUS paradigm induce?

A

Anhedonia measured by preference of a sweetened solution

55
Q

What was the symptomatic effect of viral GATA1 shRNA in the CUS paradigm?

A

It blocked the anhedonia, rats went for the sweetened solution

56
Q

Which synapse related genes are located pre-synaptically?

A
  • SYN1
  • RAB3A
  • CALM2
    and
  • PUBB 2/4
57
Q

Which synapse related genes are located post-synaptically?

58
Q

What are the two main conclusion of this study?

A
  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
Q

What conclusion from another study support the findings of Kang et al.?

A

The rapid antidepressant actions of NMDA receptor blockade are associated with increased spine number and function, and increased synaptogenesis in the PFC.

60
Q

How was the neuron culture generated?

A

Embryonic brain were prepared from fetal SD rats at 18 day gestation and mechanically triturated.

61
Q

What is the other name for viral GATA1?

A

rAAv-GATA1

62
Q

What did Sholl analysis investigate?

A

Dendritic Branching

Short Answered Question Papers (2 decks)

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