Differential effect on myelination through abolition of activity‐dependent synaptic vesicle release or reduction of overall electrical activity of selected cortical projections in the mouse

Abstract

Myelination of axons by oligodendrocytes in the central nervous system is crucial for fast, saltatory conduction of action potentials. As myelination is central for brain development and plasticity, and deficits are implicated in several neural disorders such as multiple sclerosis, major depressive disorder, bipolar disorder and schizophrenia, it is important to elucidate the underlying mechanisms regulating myelination. Numerous mechanisms have been proposed by which the communication between oligodendrocytes and active axons may regulate the onset and maintenance of activity‐dependent myelination. We compared two models of ‘silencing' layer V and/or VI cortical projection neurons from early stages by either decreasing their excitability through Kir2.1 expression, an inward rectifying potassium channel, introduced through in utero electroporation at embryonic day (E)13.5, or inhibiting regulated vesicular release through Cre‐dependent knock‐out of synaptosomal associated protein 25 kDA (SNAP25). SNAP25 is a component of the soluble N‐ethylmaleimide fusion protein attachment protein receptor (SNARE) complex, which, among others, is needed for calcium‐dependent regulated vesicle release from synapses. In layer VI cortical projection neurons in the Ntsr1‐Cre;Ai14;Snap25 fl/fl mouse, we found that inhibiting regulated vesicular release significantly decreased the amount of myelin basic protein (MBP, used as marker for myelination) and the amount of myelinated projections at postnatal day (P)14 without affecting the initial timing of onset of myelination in the brain (at P7/P8). Additionally, overall oligodendrocyte maturation appears to be affected. A strong trend towards reduced node of Ranvier (NoR) length was also observed in Ntsr1‐Cre;Ai14;Snap25 fl/fl corpus callosum. An equally strong trend towards reduced NoR length was observed in Rbp4‐Cre;Ai14;Snap25 fl/fl corpus callosum at P14, and the g‐ratio in the spinal cord dorsal column was reduced at P18. However, no measurable differences in levels of MBP were detected in the striatum when comparing Rbp4‐Cre;Ai14;Snap25 fl/fl and control brains. Conversely, Kir2.1 in utero electroporation at E13.5 did not significantly affect the amount of MBP or number of myelinated callosal axons at P14 but did significantly decrease the NoR length measured in the corpus callosum. It therefore seems likely that the excitability of the neuron can potentially perform a modulating function of myelin characteristics, whereas regulated vesicular release has the potential to have a more pronounced effect on overall myelination, but in a cell‐type specific manner.

Evidence That ITPR2-Mediated Intracellular Calcium Release in Oligodendrocytes Regulates the Development of Carbonic Anhydrase II + Type I/II Oligodendrocytes and the Sizes of Myelin Fibers

“…Our expression analyses established that Itpr2 is highly upregulated in differentiating OLs at early postnatal stages (Figure 1 and Supplementary Figure 1) when oligodendrocytes undergo active differentiation and myelination (Franco-Pons et al, 2006;Korrell et al, 2019). In fact, its expression is not detected in immature OPCs in embryonic tissues and is downregulated after axonal myelination in adult tissues (Figure 1 and Supplementary Figure 1).…”

“…To assess the in vivo role of Itpr2 in regulating OLs differentiation and myelin development, we next examined the expression of mature OL marker Plp1 in postnatal brain tissues by ISH. It was found that the number of Plp1 + myelinating OLs in Itpr2 –/– corpus callosum was significantly lower than that of controls between P7 and P15 stages ( Figures 2A–B′,D ) when OLs undergo active differentiation and myelination in this region ( Franco-Pons et al, 2006 ; Korrell et al, 2019 ). Intriguingly, the number of Plp1 + OLs was not altered in P21 control and mutant tissues ( Figures 2C,C′,D ).…”

Myelin Plasticity and Repair: Neuro-Glial Choir Sets the Tuning

“…Indeed, myelin sheath length can be remodeled once it is established; however, these changes are relatively rare in adulthood and sensory enrichment failed to induce any measurable changes in sheath length in rodents (Hill et al, 2018;Hughes et al, 2018). Alternatively, conduction velocity could be tuned by changes in nodal gap length, which can be modulated in adult mice (Dutta et al, 2018), upon neuronal activity changes (Cullen et al, 2019;Korrell et al, 2019).…”

Completion of neuronal remodeling prompts myelination along developing motor axon branches

“…In addition, recent observations in the central nervous system (CNS) indicate that myelin contributes to fine-tuning of neural circuits ( Fields, 2015 ; Chang et al, 2016 ; Kaller et al, 2017 ). For instance, myelin sheaths and nodes of Ranvier, ion channel–enriched axon segments interspersed between myelin sheaths, show activity-dependent plasticity ( Huff et al, 2011 ; Gibson et al, 2014 ; Mensch et al, 2015 ; Etxeberria et al, 2016 ; Korrell et al, 2019 ; Bacmeister et al, 2020 ) that appears to shape “patchy” myelination patterns in neocortex ( Tomassy et al, 2014 ). While activity-regulated myelination is less studied in the peripheral nervous system (PNS; Stevens and Fields, 2000 ; Fields, 2015 ), in the PNS, the axon–glial unit is more accessible than in the CNS, and the signaling pathways governing peripheral myelination are better understood ( Taveggia et al, 2010 ; Pereira et al, 2012 ; Grigoryan and Birchmeier, 2015 ).…”