Module 11 - Microglia Flashcards
how many more glia are there compared to neurons?
10-50x more glia than neurons
what are the 4 classes of glial cells?
- Astrocytes (derived from neuroepithelium)
- Microglia (related to macrophages, mesodermal)
- Oligodendrocytes (CNS, derived from neuroepithelium)
- Schwann Cells (PNS, derived from neuroepithelium, neural crest)
which type of glial cells are myelinated?
oligodendrocytes and schwann cells
what’s the difference between CNS and PNS?
CNS is enveloped in bone, the PNS is not
what are astrocytes?
star shaped cells with end-feet that contact capillaries or neurons; part of the blood-brain barrier
what is astrocytes function?
bring nutrients into the CNS and to prevent the entry of many compounds into the CNS
what chemical’s extracellular levels are controlled by astrocytes?
potassium; astrocytes can take up lots of potassium released by neuronal activity
astrocytes are the only cell type that can store what molecule?
glycogen; it can supply neurons with glucose and lactate
what can astrocytes supply neurons with?
glucose and lactate
name a marker for astrocytes
GFAP: glial fibrilary acid protein
what does myelin provide to cells?
electrical insulation wrapped around the axons
what kind of animals have myelin?
vertebrates only!
are dendrites myelinated?
no; only axons (not all axons tho)
what are nodes of ranvier?
highly specialized region of the axonal membrane that is not myelinated
what is concentrated at node of ranvier? why?
Voltage gated sodium channels: they regenerate APs between myelin sheath
how long are each segments (one Schwann cell) of myelin along a peripheral nerve?
about 1mm long
what is a oligodendrocyte?
CNS Myelinating Glia
what is different between Schwann cell and oligodendrocyte?
oligodendrocyte (CNS) can myelinate multiple axons simultaneously
how many axons are myelinated per one oligodendrocyte approximately?
15 axons
how long can internode be?
varies: from 10s of microns to 100 microns
are all oligodendrocytes myelinating?
no; there are many perineural non-myelinating oligodendrocytes
how was the existence of oligodendrocytes proved?
via staining techniques that selectively visualized these cells
Where do Schwann cells come from?
Neural crest: Born in neural epithelium and migrate out of the neural tube (CNS) to myelinate axons in peripheral nervous system (PNS).
Where do Oligodendrocytes come from?
Born as oligodendrocyte precursor cells (OPCs) in the ventricular zone at several places along the neural tube, and then migrate and proliferate to populate all myelinated regions of the CNS.
more precisely what are the steps of oligodendroglial development in
the mammalian spinal cord?
- OPCs born in ventricular zone
- OPC migration
- OPC proliferation
- Differentiation to post-mitotic but pre-myelinating oligodendrocytes
- Establishment of contact with axons, myelin formation and elimination of superfluous oligodendrocytes by apoptosis.
what happens to not yet mature oligodendrocytes that don’t contact an axon?
they die
where do OPCs migrate to?
to where there are most axons
what is PDGFalphaR?
platelet derived growth factor receptor: unique OPC marker
where are OPCs born?
ventral midline of the embryonic spinal cord, just dorsal to the floor plate.
in what directions do OPCs migrate to after their birth?
migrate dorsally away from the floor plate (FP)
what are netrins?
Secreted Chemotropic Guidance Cues for Cell and Axon migration (direct axon migration during neural development)
what proteins are netrins related to?
laminins
where is netrin-1 found?
it is made in the floor plate at the ventral midline and is secreted to form a ventral to dorsal gradient
what are netrins vs laminins average size?
netrins are 75kDa,
laminins are 800 kDA
netrin secretion makes the ECM _______
polarized
what are the 2 netrin receptors families and their function?
DCC: attraction to netrin-1 (growing towards netrin gradient)
UNC5: (homologs A-D) required for repulsion to netrin-1 (growing away from netrin)
do OPCs express netrin-1? what do they express?
no; they express DCC and/or UNC5A & B (netrin receptors)
what happens to cells that make both DCC and UNC5?
they have the capacity to respond to netrin-1 as an attractant or a repellent
how do netrin direct axon migration? what else do they influence?
- via cytoskeletal organization
- influence cell-substrate and cell-cell adhesion
Netrin-1 repels oligodendrocyte precursor cells away from the _____ _______ directing them toward _____
ventral midline;
axons (future white matter)
name other extracellular guidance cues that direct OPCs migration
long or short-range repellents, long or short-range attractants
where are sodium channels concentrated?
at the node (between myelinated internode)
where are potassium channels found?
in the juxtaparanode (under compact myelin)
where is Caspr located?
at the paranode on the axonal surface
what is the major axis of polarization of a myelinating glial cell?
the cell-body verses the myelin membrane
the myelin sheath is sub-divided in what kind of regions?
compact and non-compact membrane regions
what does MBP mark?
compact myelin membrane (internode)
what is TMEM10 a marker for?
(type 1 transmembrane protein); not associated with compact myelin
explain the myelin formation process
generation of the spiral wrap of the membrane (inner tongue wraps around);
compaction of myelin
what is the g-ratio? what is the optimal value?
axon diameter / total outer diameter;
normal (optimal) = 0.6-0.8
how is g-ratio maintained?
ticker axons have ticker myelin
describe myelin composition
similar to PM; 80% lipid, 20% proteins, high cholesterol and glycolipids
what is sphingomyelin composed of?
sphingosine (lipid) and phosphocholine (hydrocarbon and nitrogen)
what chain strengthens myelin?
sphingomyelin hydrocarbon chains extending from the lipid bilayer
what did the synthetic fiber experiment show?
oligodendrocytes will make myelin wraps even without a living axon!
what does it mean that oligodendrocytes myelinate even a synthetic fiber?
they don’t need a specific signal to form compacted myelin
what is PMP22 responsible for?
it is the genetic basis for Charcot Marie tooth disease
describe myelin structure
compacted lipid bilayer
where is MBP found?
intracellular face of the PM; it is membrane-associated
what is MBP function?
zipping the cytoplasm; bring the 2 membranes together, acting like a molecular bridge
what % of myelin proteins are MBP?
30%
what % of myelin proteins are PLP?
50%
what is PLP role?
linking and compacting the extracellular face of the plasma membrane
where is PLP translated?
at the rER
where is PLP located?
it is stored in late endosomal compartment until it is recruited to the PM after trigger from contact with an axon
where is MBP translated? why?
locally near its point of insertion in the PM; this prevents inappropriate membrane compaction
what is multiple sclerosis caused by?
abnormal myelin, leading to decrease in axon conduction velocity and major disruptions of neuronal function in the brain
what happens when you inject MBP into a mouse?
experimental allergic encephalomyelitis (EAE), characterized by loss of CNS myelin due to a immune response against MBP (experimental model of multiple sclerosis)
what is the shiverer mouse?
a mouse with a deletion mutation of the MBP gene that produces tremors, convulsions, early death
how can the shiverer mouse’s phenotype be rescued?
transgenic addition of a copy of the MBP gene
what happens to PMP22 in CMT (charcot-marie-tooth)?
it is duplicated (increase in gene dosage)
what are CMT disease characteristics?
cycles of demyelination and remyelination, weakness, greatly decreased conduction velocity in the peripheral nerves
when does myelination start?
post birth
why do we have myelin precursor cell our whole life?
because we add and loose myelin throughout our life
what are Leukodystrophies?
A group of genetic disorders that effects the development and maintenance of myelin
what happened when they transplanted human OPCs in an immunodeficient shiverer mice?
MBP came back and myelination was rescued
what are microvilli specific to?
specific to schwann cells, found at node of ranvier
are schwann cells or oligodendrocytes bigger?
schwann cells are 10x bigger
what is found at the dynamic leading edge of a schwann cell?
F-actin
describe the process of Caspr spiral consolidation
asymetric process; fronts of 2 schwann cells extend towards eachother, forming a spiral that disappears in mature node
what proteins do NA but not K channels bind?
ankyrin
what junctions are involved in anchoring paranodal loops to the axon and to eachother?
gap, thigh junctions between the myelin loops.
axo-glial adhesions between the paranodal channels and the axon
what is the axo-glial adhesion junction made of?
Caspr, CNTN1 (contactin), NF155 (Neurofascin155)
what happens after genetic deletion of caspr, NF155 or CNTN?
- disruption of paranodal junctions and disorganization of the specialized domains along axons: no more boundary between paranode and juxtaparanode and node
- balance and coordination deficit
- reduced conduction velocity
what kind of junctions do tight and gap junctions form between paranodal loops?
autotypic junctions
what is claudin 11?
tight junction protein also called OSP oligodendrocyte specific protein
what happens if you KO DCC? what does this show?
disruption of paranode maintenance; DCC is required to maintain axoglial parnodal junctions in the mature CNS
what happens to Caspr in DCC KO?
Caspr distribution slides along the axon
what happens to Na+ and K+ channels in netrin and DCC KO?
abnormal distribution
how does selective deletion work? what was it used for?
selectively deleting floxed DCC allele in oligodendrocytes with tamoxifen regulated cre-recombinase
what did DCC tamox induced deletion show?
paranode disruption aka DCC is essential for paranode
what does UNC5B deletion cause?
everted paranodal loops, reduced claudin 11 levels, disruption of junction between loops
what structures are made of non-compacted myelin?
Paranodal loops, Cajal Bands and Schmidt-Lantermann Incisures
what are Cajal bands and S-L incisures for?
traverse compact myelin to connect cell body cytoplasm with the paranodal loops
what does loss of Periaxin do?
loss of cajal bands, reduced internode length, slower conduction rate -> severe PNS demyelination neuropathy
where is periaxin found?
at the junction of compact myelin and PM
what organelle can travel through myelin via cytoplasmic channels?
mitochondria (cus they can divide and fuse, also channel can enlarge)
