Oligodendrocyte progenitor cells Flashcards
Brain distribution, identifying characteristics
Main proliferating cell type in CNS Equally distributed throughout brain NG2 and PDGFR-alpha positive 5% total cells in the brain Morphology similar to ramified microglia Sit in a network, but no gap junctions Regenerative - Kirby et al 2006 - laser ablation of an area of OPCs causes repopulation with more OPCs Zhu et al 2008 - can differentiate into oligodendrocytes or into astrocytes!
Channels and receptors expressed by OPCs
All three types of glutamate receptors (AMPA, NMDA, kainate)
Some have voltage gated sodium channels, some do not. The ones that do can fire APs, but these are only found at peak myelination point in development
All OPCs have a sodium current, but don’t all fire APs.
There’s no evidence that the APs can propagate between OPCs.
Neuro-glial synapses (6)
Kukley et al 2007 - found vesicular glutamate release from axons in the white matter. This glutamate bound to ionotropic receptors on OPCs. These are the only neuro-glial synapses in the nervous system.
Ge et al 2006 - synaptic contacts between axons and NG2+ glia remain even when the glia are dividing
Karadottir et al 2008 - OPCs expressing voltage gated Na channels can fire APs upon synaptic input by an unmyelinated axon, or unmyelinated part of a partially myelinated axon.
Kukley et al 2010 - These synaptic inputs disappear when the OPC differentiates into a PLP+ oligodendrocyte, despite retaining AMPA and GABA receptors.
Synaptic contacts with demyelinated neuron increase prior to remyelination
Ge et al 2009 - These neuro-glial synapses can undergo LTP.
Gibson et al 2014 - proliferation of OPCs is regulated by neuronal activity
Lin et al 2005 - Each OPC may have many synapses onto it - one estimate suggested 70 synapses from a single climbing fibre onto a OPC. Some may receive from more than one CF (unlike Purkinje cells). Glutamate release from CF causes fast AMPA-mediated currents, but not APs.
White matter plasticity - evidence of it
Seidl 2014 - Different length neurons in the cochlea have different myelination patterns, to allow for differences in propagation and sound localisation. The longer axon has changes in axon diameter and nodes more distantly spaced, to speed up transmission.
McKenzie et al 2014 - motor learning requires active central myelination. Myelination increases while learning to run on a complex wheel.
Myelination also increases while learning juggling, playing the piano, and reaching
Keas 1907 - myelination continues into late adulthood
Adults get about 0.3% oligodendrocyte turnover each year, but myelin is turned over much quicker.
How is differential myelination regulated? Evidence for activity dependent
Demerens et al 1996 - TTX blocks myelination of the optic nerve. Alpha-scorpion toxin, which increases frequency of APs, increased myelination 2.4 times.
Sholz et al 2009 - diffusion tensor imaging showed adult humans undergo changes in white matter while learning to juggle. This was the first evidence of adult white matter plasticity in vivo.
OPC populations transiently decrease immediately after training
McKenzie et al 2014 - Blocking adult production of oligodendrocytes impairs mice learning to run on a complex wheel.
The speed of white matter changes after training is comparative to dendritic spine changes in synaptic plasticity
How is differential myelination regulated? Evidence against activity dependent
Oligodendrocytes can myelinate nanofibres in vitro
Knocking out AMPARs and NMDARs in OPCs will slow myelination but not prevent it.
Blocking vesicular glutamate release in the optic nerve caused the same number of axons to be myelinated, but with smaller gaps between nodes.
How is differential myelination regulated? Evidence for the existence of early activity-independent and late activity-dependent myelination
Knocking out Erbb3 (the neuregulin receptor) has little effect on developmental (activity-independent) myelination, but blocks activity-dependent myelination —> ‘social isolation’ phenotype
Thinner myelin develops when Erbb3 is blocked later in development, but no major alterations in myelin were apparent when is was blocked early on. So maybe you need glutamate at first, then neuregulin?
Adding Neuregulin (aka NRG1) or BDNF to dorsal root ganglion OPC-neuron cultures induces a switch from activity independent to dependent myelination. It also alters subunit composition of NMDARs, rendering the OPCs more sensitive to glutamate signalling
NRG1 expression is itself upregulated by neuronal activity, so maybe NRG1/Erbb3 plays its role once circuits have matured and become active
Activity-dependent remyelination
Blocking glutamate receptors in a demyelinated lesion prevents OPC differentiation and remyelination
Axon-OPC synapses are upregulated after demyelination
/How/ might activity-dependent myelination be possible?
L1 is an axonal surface protein, regulated by neuronal activity patterns. Blocking it prevented initiation of myelination. But beware, nerve stimulation downregulated L1, not up. So it’s about patterns, not overall expression
Reinitiating myelination from a mature oligodendrocyte
Constitutive activation of Akt in mice oligodendrocytes causes continued myelination throughout life span
Tamoxifen-induced deletion of PTEN (which inhibits this pathway) reinitiates myelination in the adult
Experimental increases in PIP3 and activation of Akt in myelination oligodendrocytes reopens cytoplasmic channel and reinitiated myelin growth (Snaidero et al., 2014), potentially allowing remodelling of the existing myelin sheath?
Overall, activation of PI3K/Akt pathway causes hypermyelination
Neuregulin induced myelination in vitro is mediated via this pathway (Lundgaard et al., 2013), and glutamate signalling activates Akt via mGluR1 (Gallo et al., 1994)!
