Periaxonal and nodal plasticities modulate action potential conduction in the adult mouse brain

Cullen, Carlie L.; Pepper, Renee E; Clutterbuck, Mackenzie T.; Pitman, Kimberley A; Oorschot, Viola; Auderset, Loic; Tang, Alexander D.; Ramm, Georg; Emery, Ben; Rodger, Jennifer; Jolivet, Renaud; Young, Karen

doi:10.1016/j.celrep.2020.108641

Cited by 75 publications

(84 citation statements)

References 95 publications

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“…Overall, these data suggest that slc12a2b can compensate for the slc12a2 loss, while slc12a2 is not sufficient to compensate the slc12a2b zebrafish mutation. The potential impact of the axomyelinic swelling detected in mice and zebrafish with decreased expression of TET1 or its gene target Slc12a2, has been highlighted by a recent report that changes in the space surrounding the axon, may decrease the speed of axial conduction of the action potential 77 . Collectively, these findings suggest that the agedependent decline of TET1, by altering the axo-myelinic junction, may further slowdown axonal conductance.…”

Section: Discussionmentioning

confidence: 99%

TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

et al. 2021

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The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier (Slc) gene family. Among them, we show that the expression levels of the Na+/K+/Cl− transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface.

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Section: Discussionmentioning

confidence: 99%

TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

et al. 2021

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“…Although most work has focused the longitudinal current flow along the interior of the axon, a recent study indicates that conduction velocity is also influenced by current flow through the periaxonal space between the innermost myelin wrap and the axon (Cohen et al, 2020). This may prove to be highly significant in light of findings that the width of this space is regulated by neuronal activity and during learning (Cullen et al, 2021).…”

Section: Myelinating Glia Organize the Axonmentioning

confidence: 99%

Neuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons

Duncan

Simkins

Emery

2021

Front. Cell Dev. Biol.

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The myelination of axons by oligodendrocytes is a highly complex cell-to-cell interaction. Oligodendrocytes and axons have a reciprocal signaling relationship in which oligodendrocytes receive cues from axons that direct their myelination, and oligodendrocytes subsequently shape axonal structure and conduction. Oligodendrocytes are necessary for the maturation of excitatory domains on the axon including nodes of Ranvier, help buffer potassium, and support neuronal energy metabolism. Disruption of the oligodendrocyte-axon unit in traumatic injuries, Alzheimer’s disease and demyelinating diseases such as multiple sclerosis results in axonal dysfunction and can culminate in neurodegeneration. In this review, we discuss the mechanisms by which demyelination and loss of oligodendrocytes compromise axons. We highlight the intra-axonal cascades initiated by demyelination that can result in irreversible axonal damage. Both the restoration of oligodendrocyte myelination or neuroprotective therapies targeting these intra-axonal cascades are likely to have therapeutic potential in disorders in which oligodendrocyte support of axons is disrupted.

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“…We repeated this procedure for 60 myelin gaps across several fields of view of a P246 mouse to produce the histogram shown in Figure 2I with an average gap length of 2.04 ± 0.76 µm. This is longer than the published length of ~1 µm for Nodes of Ranvier, 46 , suggesting that our SRS measurements include paranodal length as well.…”

Section: Resultsmentioning

confidence: 56%

In Vivo Simultaneous Nonlinear Absorption Raman and Fluorescence (SNARF) Imaging of Mouse Brain Cortical Structures

Manifold

et al. 2021

Preprint

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Two photon excited fluorescence (TPEF) microscopy is a widely used optical imaging technique that has revolutionized neurophotonics through a diverse palette of dyes, specialized transgenic models, easy implementation, and straightforward data analysis. However, in vivo TPEF imaging is often limited in the number of contrasts available to distinguish different cells, structures, or functions. We propose using two label free multiphoton microscopy techniques: stimulated Raman scattering (SRS) microscopy and transient absorption microscopy (TAM) as complementary and orthogonal imaging modalities to TPEF for in vivo brain imaging. In this study, we construct a simultaneous nonlinear absorption, Raman, and fluorescence (SNARF) microscope and image several cortical structures up to 250-300 μm below the pial surface, the highest reported in vivo imaging depth for SRS or TAM. We further demonstrate the capabilities of our SNARF microscope through the quantification of age-dependent myelination, hemodynamics, vessel structure, cell density, and cell identity in vivo. Using machine learning, we report the use of label free SRS and TAM features to predict capillary lining cell identities with 90% accuracy. The SNARF microscope and methodology outlined herein provide a powerful platform to study several research topics, including neurovascular coupling, blood brain barrier, neuronal and axonal degeneration in aging, and neurodegenerative diseases.

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Periaxonal and nodal plasticities modulate action potential conduction in the adult mouse brain

Cited by 75 publications

References 95 publications

TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

Neuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons

In Vivo Simultaneous Nonlinear Absorption Raman and Fluorescence (SNARF) Imaging of Mouse Brain Cortical Structures

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