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Neuroscience > Lecture #8 > Flashcards

Lecture #8 Flashcards

1
Q

what are microglia?

A

a specific subset of myeloid cells in organs that are ready to be activated when bacteria or viruses enter the organ

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2
Q

where do microglia come from?

A

forerunners are coming from a specific subset of progenitors that are hosted in the yolk sac in specific cellular islands

from the yolk sac these cells migrate to the initial rudimental circulation and then to the brain

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3
Q

how do the initial progenitors connect to the final formation of the brain?

A

the initial population can support the generation of all microglial cells in the brain

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4
Q

what is a critical molecular axis for the maintenance of microglial cells?

A

CSFR1 and its ligand CSF1

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5
Q

what happens if CSFR1 is not present?

A

microglia cannot develop

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6
Q

what is the function of PU.1?

A

another transcription factor relevant for myeloid cells and for the maintenance of microglial progenitors

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7
Q

why can microglial progenitors enter after day 11?

A

the presence of the forming BBB is enough to block the further infiltration of microglial progenitors from the yolk sac to the brain

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8
Q

what is the difference between the brain and other tissues of the body in regards to the myeloid population?

A

the brain is the only organ in which we have a population of myeloid cells that can self-sustain along the entire life, while in other organs the current hematopoiesis can generate myeloid cells to replenish the tissue macrophages

tissue resident macrophages are a mixed population

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9
Q

what is parabiosi?

A

when two mice are joined using surgery via their blood circulations

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10
Q

what was parabiosi used to discover?

A

in some pathological conditions we have the infiltration of blood born cells, and in others this infiltration is not needed

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11
Q

what happens to GFP positive cells in conditions of neuroinflammation?

A

they are able to remain in the CNS for a relatively short period of time, and after this time they disappear

during this period of time they start to acquire a cell morphology which is to different from activated microglia, but they are not microglia, therefore they are not allowed to stay in the microglia

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12
Q

during early embryonic development, we have the neural plate, and in a specific region of the CNS we have the tube, at this point what is there a tight association between?

A

the formation of neuroepithelial cells and the infiltration of microglia

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13
Q

what is one key function of microglia in the post-natal brain?

A

they are constantly scanning the environment exerting both surveillance and patrolling

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14
Q

how do microglia constantly monitor their surroundings?

A

they constantly extend and retract their fine cellular processes at a rate of a few micrometers per minute to scan the parenchyma

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15
Q

in the presence of pathological conditions, what to microglia do?

A

they can send cytoplasmic bundles to the regions in which there is damage with the final goal to confine the damage and block its spread

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16
Q

what is another unique characteristic of these cells in relation to their distribution?

A

they are distributed in the CNS but never overlap → the density of these cells is fundamental to their function

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17
Q

what portion of the CNS do microglial cells make up?

A

5-13%

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18
Q

how do microglial cels contribute to brain physiology / pathology in regards to physical interactions?

A

they can interact with neurons and with ding cells contributing to the phagocytosis of debris or dying cells themselves

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19
Q

how do microglial cels contribute to brain physiology / pathology in regards to the release of soluble factors?

A

if we kill microglia, we will have some neurological deficits that are due to the degeneration of some specific neuronal subtypes, suggesting that microglia exert trophic action for these neurons

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20
Q

what function do microglia exert that is particularly important during pathologies involving death, when debris has to be removed as well as during development?

A

phagocytosis

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21
Q

what do microglia secrete?

A

several soluble facts including a multitude of growth factors, neurotransmitters, cytokines, and chemokine

22
Q

what is the lifespan of microglia in humans?

A

~ 4 years

23
Q

virtually all microglia in the brain are positive for which fractal kinase receptor?

A

CX3CR1

24
Q

which method activates the diphtheria toxin (DTx) allowing scientists to deplete approximately 90% of microglia?

A

transgenic mice that express CreER:iDTR

25
Q

what happens when microglial are killed?

A

the few remaining cells start to work like progenitors and start to become very fast proliferators

regenerate the population in ~ 5 days

26
Q

what does the repopulation of the system after treatment with something like Ganciclovir?

A

depends on the infiltration of the myeloid cells from the periphery because with this treatment the BBB permeability can be altered

26
Q

what does the repopulation of the system after treatment with something like Ganciclovir?

A

depends on the infiltration of the myeloid cells from the periphery because with this treatment the BBB permeability can be altered

27
Q

which receptor is fundament for microglial homeostasis?

A

CSF1 → if this receptor (ligand) is inactivated you kill all of the microglia

28
Q

what happens when the remaining microglia sense the environmental lack of microglia?

A

they switch the kinetic features from a very long lasting semi-quiescent cell population to a fast proliferating state

29
Q

which ligand and receptor are important for avoiding unwanted microglial activation in physical conditions?

A

CD200 ligand and CD200 receptor

30
Q

when do neurons express CD200?

A

when they want to keep the microglia in resting conditions → they want to avoid activation that can be toxic for the system, because the cells release a huge number of proinflammatory signals in the extracellular space exerting a toxic function on neurons

31
Q

what is the most famous example of a region-dependent neurotransmitter expression in microglia?

A

only microglia in the striatum express dopamine receptors, because it is the only place where neurons release dopamine

32
Q

what else can microglia sense in a region-dependent manner?

A

neurotransmitters and diffusible signals such as chemokine and cytokines

33
Q

describe synaptic pruning during development:

A

during the embryonic stages the neurons generate a large number os synapses, many of which are not strong enough to survive and the system must remove them

34
Q

what was the first drug used as a blocker of sodium voltage gated channels in the axon hillock, when studying the retina of mice?

A

TTX (tetrodoxin) - the blockage of this channel causes the blockage of action potential generation → a large number of synapses in the CNS (thalamus) start to become weak

35
Q

where is tetrodoxin isolated from?

A

pufferfish

36
Q

what did they find in mice when TTX was injected?

A

the percentage of engulfment of post-synaptic proteins was significantly increased in microglia from animals treated with TTX

37
Q

what small molecule was also injected which has the opposite function of TTX?

A

forskolin → causes an increase in synaptic transmission

38
Q

describe the molecular mechanism used to remove weak synapses:

A

the weak synapse starts to express the complement receptor of the compliment ligand (C3) on the surface → when the compliment receptor engages the ligand, the microglial cells start to engulf the synapses, and it starts to remove the pre-synaptic and post-synaptic terminals

(since microglia are expressed on the tip of the cytoplasmic bundles o the cell surface, the tips are continuous looking for dangerous signals in the environment because these cells express the complement receptor (CR3))

39
Q

what might issues with synaptic pruning lead to?

A

several brain disorders

40
Q

what was observed with CSFR1R was knocked out in mice?

A

there was a 50% reduction in cortical thickness and therefore a reduction in cortical neurons

41
Q

what did they contribute this drastic reduction of cortical neurons to?

A

suggests that microglial cells probably exert some trophic factors or neurons, and if these microglia are removed you lose this topic factor

42
Q

where specifically were microglia found during embryonic development?

A

virtually al microglia are in the terminal niche in the brain, and appears that they exert trophic (functional) activates in the very same neurogenic niches in which we described the asymmetric and symmetric cell divisions

43
Q

what was found when the phagocytic activity of microglia is deactivated?

A

you end up with a significant increase in the number of cortical brain neurons

44
Q

what happens if you overactive microglia (with some LPS)?

A

it induces aberrance in a significant way, leading to a reduction in neonatal precursors

45
Q

what is happening if we are in the presence of a chronic neurodegenerative disorder like Parkinson’s or Alzheimers?

A

there is irreversible CNS damage and persistent inflammation, where the persistent microglial activation is considered the driver

there is a dramatic alteration in cell morphology in the chronic condition of the microglia

46
Q

describe the “amend cell morphology” that microglia acquire under chronic pathological conditions:

A

cells retract the cytoplasmic bundles and start to acquire a rod shape

47
Q

describe the original focus of M1 activation in microglia:

A

fight against bacteria: these cells start to express ROS, Proinflammatory cytokines, and chemokines with the final activation being cytotoxic activation = tissue injury

48
Q

describe the original focus of M2 activation:

A

protective activation: cells release IL-10, arginase, and trophic factors in the extracellular space

fundamental for immunosuppression and to induce tissue repair

49
Q

describe the current view of microglial activation:

A

occurs in response to tissue damage, but the activation is a spectrum, not a clear M1 or M2 polarization → something overall in between and plastic

50
Q

describe the long vs short activation of microglia:

A

if the activation time is short microglia can be activated but return to the resting state

if there is a long chronic activation cells start to acquire the characteristics of an M1-like cell

51
Q

in a transgenic mouse model with autotrophic lateral sclerosis, what do the activated microglial cells look like?

A

typically activated towards something that is M1-like → if you purify these cells from the spinal cord and analyze them using a classic real-time pro-inflammatory markers the vast majority of these cells will be TNF positive and therefor secrete want pro-inflammatory signals

this led to the M1/M2 paradigm to be changed

Neuroscience (19 decks)

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