Microglia and oligodendrocytes Flashcards Preview

N2 > Microglia and oligodendrocytes > Flashcards

Flashcards in Microglia and oligodendrocytes Deck (11):
1

Microglia development

Chan et al 2007 - They are the first glial cells to enter the brain, and develop alongside neurons. They enter in two waves, the first slow and driven by proliferation, the second fast and driven by invasion
Are 10% of brain cells, express neurotransmitter receptors

2

Microglia development

They migrate from a distinct lineage of progenitors in yolk sac, self-renew from resident population in adults. Note that Chen et al 2010 suggested at least a proportion come from bone marrow. But tricky to tell whether these are true microglia or just infiltrating macrophages
Ajami et al 2011 - infiltrating monocytes causes experimental autoimmune encephalitis progression, but do not contribute to microglia pool.
During development, they go from a ‘voracious monster’ morphology, with large round cell bodies, to a ‘ramified/surveillant’ morphology, with a small rod-shaped body and tendril-like processes. They may have both an inflammatory and anti-inflammatory phenotype.

3

Microglia in brain injury and illness

in the healthy brain they're mostly ramified (though processes are constantly moving), but become 'activated' in e.g. encephalitis, to produce IL-6 and TNFalpha etc. Davalos et al 2005 - When activated by acute injury, they immediately send all their processes towards the injured cell and bodies become rounder. Pipette filled with ATP has the same effect, so this must be the signal.
Some think there are anti-inflammatory M2, and pro-inflammatory M1, but this is being debated (many think there are way more complex subpopulations)

Steiner et al 2008 - Microglia are activated in schizophrenia, and in dlPFC and hippocampus of patients who killed themselves during psychotic episode, there's higher density of microglia.

4

Microglia influence on behaviour

Steiner et al 2008 - Microglia are activated in schizophrenia, and in dlPFC and hippocampus of patients who killed themselves during psychotic episode, there's higher density of microglia.
Chen et al 2010 - Hoxb8 is expressed by a subpopulation of microglia. Hoxb8 mutants show compulsive grooming. Bone marrow transplant from WT rescued this behaviour. Cells of all haematopoeitic lineages express Hoxb8, and Hoxb8 mutants had 15% reduction in microglia. BUT did they actually add normal microglia with this transplant? Or could it have been general disruption of the immune system, given gut-brain interactions?
Zhan et al 2014 - mice with a mutant chemokine receptor have a transient reduction in microglia during development, and consequently reduced synaptic pruning later. They exhibit deficits in synaptic transmission, functional connectivity, and social interactions. Increased repetitive-behaviour phenotypes that had previously been associated with autism and other disorders.
Derecki et al 2012 - MeCP2 mutation causes Rett syndrome, an ASD with dendritic and synaptic abnormalities. MeCP2 loss in mice mimics the disease. WT bone marrow transplantation causes engraftment of MeCP2-expressing microglia into the parenchyma, and reverses the brain effects. This supports Chen et al's assumption too.

5

Microglia in development

Depleted microglia result in an increase in neural precursor cells, and absence of microglia results in abnormal outgrowth of dopaminergic neurons towards the striatum and abnormal localisation of subcortical interneurons.
Zhan et al 2014 - reducing microglia entry to brain in development reduces synaptic pruning, and results in deficient functional connectivity.

6

Microglia and synapses - acute effects

Tremblay et al 2010 - light deprivation altered microglia morphology, with more processes apposed to synaptic clefts, and more phagocytic structures. Light exposure reversed this. So there's rapid microglia response to altered neuronal activity.
Parkhurst et al 2013 - if you kill microglia in the adult, nothing happens at first, but then mice are harder to train in tasks.

7

Myelination process

Snaidero et al 2014 - used live imaging, high pressure freezing microscopy and a virus as a reporter. Found that new myelin is added at the inner tongue, whilst newly formed layers extend laterally to form a series of paranodal loops. Cytoplasmic channels enable membrane trafficking to the inner tongue. These channels close during development, but can be reopened by PIP3 application, which also stimulates myelin formation.

After myelination is done, there may be a developmental switch from turning pyruvate into fatty acids and myelin, to turning it into lactate, to 'feed' the neuron. If you knockout lactate transporters in the oligodendrocytes, you get large and degenerating axons.

8

Importance of myelination

Shiverer mice, with no Myelin Basic Protein, have myelin that won't compact. Shiver and die 3 weeks after birth.
Jimpy mice, with mutation in proteolipid protein, myelin just disintegrates. Intention tremour, convulsions, death within 4 weeks. Most PLP mutations (inc in humans) cause hypomyelination, glial cell proliferation, oligodendrocyte death. Gene is dosage dependent; animals that overexpress it start normal but then spontaneously demyelinate.

9

Node structure

Voltage gated sodium channels are concentrated at the node, with K channels concentrated at the juxtaparanodal region. Separated by an axo-glial contact at the paranode, which is mediated by Caspr and contactin among others.
All this is regulated by the oligodendrocyte (via diffusible factors) or Schwann cell (which requires contact)
New theories suggest this may be plastic - see white matter plasticity in OPC notes

10

Oligodendrocytes and neurodegeneration

Killing oligodendrocytes in the adult does nothing at first, then causes neurodegeneration.
Oligodendrocytes can regenerate in the adult, from OPCs, in demyelinating disease. But remyelination is rarely as effective or thorough as initial myelination, due to interference from inflammatory milieu.
Lactate transporter KO in oligodendrocytes causes large and degenerating neurons

11

Schwann cells vs oligodendrocytes

Oligos myelinate multiple axons, Schwann cells one.
Schwann cells myelinate with a thick layer of myelin, Oligos with thin.
Schwann cells can de-differentiate and perform many functions to allow nerve regeneration in the PNS.
Schwann cells require contact, Oligos diffusible proteins (for targeting channels to parts of the nodal structure, etc)