How Do Cells of the Oligodendrocyte Lineage Affect Neuronal Circuits to Influence Motor Function, Memory and Mood?

Oligodendrocyte progenitor cells (OPCs) are immature cells in the central nervous system (CNS) that can rapidly respond to changes within their environment by modulating their proliferation, motility and differentiation. OPCs differentiate into myelinating oligodendrocytes throughout life, and both cell types have been implicated in maintaining and modulating neuronal function to affect motor performance, cognition and emotional state. However, questions remain about the mechanisms employed by OPCs and oligodendrocytes to regulate circuit function, including whether OPCs can only influence circuits through their generation of new oligodendrocytes, or can play other regulatory roles within the CNS. In this review, we detail the molecular and cellular mechanisms that allow OPCs, newborn oligodendrocytes and pre-existing oligodendrocytes to regulate circuit function and ultimately influence behavioral outcomes

How Does Transcranial Magnetic Stimulation Influence Glial Cells in the Central Nervous System?

Transcranial magnetic stimulation (TMS) is widely used in the clinic, and while it has a direct effect on neuronal excitability, the beneficial effects experienced by patients are likely to include the indirect activation of other cell types. Research conducted over the past two decades has made it increasingly clear that a population of non-neuronal cells, collectively known as glia, respond to and facilitate neuronal signalling. Each glial cell type has the ability to respond to electrical activity directly or indirectly, making them likely cellular effectors of TMS. TMS has been shown to enhance adult neural stem and progenitor cell proliferation, but the effect on cell survival and differentiation is less certain. Furthermore there is limited information regarding the response of astrocytes and microglia to TMS, and a complete paucity of data relating to the response of oligodendrocyte-lineage cells to this treatment. However, due to the critical and yet multifaceted role of glial cells in the CNS, the influence that TMS has on glial cells is certainly an area that warrants careful examination

Low Density Lipoprotein-Receptor Related Protein 1 Is Differentially Expressed by Neuronal and Glial Populations in the Developing and Mature Mouse Central Nervous System.

The low density lipoprotein-receptor related protein 1 (LRP1) is a large endocytic cell surface receptor that is known to interact with a variety of ligands, intracellular adaptor proteins and other cell surface receptors to regulate cellular behaviours ranging from proliferation to cell fate specification, migration, axon guidance, and lipid metabolism. A number of studies have demonstrated that LRP1 is expressed in the brain, yet it is unclear which central nervous system cell types express LRP1 during development and in adulthood. Herein we undertake a detailed study of LRP1 expression within the mouse brain and spinal cord, examining a number of developmental stages ranging from embryonic day 13.5 to postnatal day 60. We report that LRP1 expression in the brain peaks during postnatal development. On a cellular level, LRP1 is expressed by radial glia, neuroblasts, microglia, oligodendrocyte progenitor cells (OPCs), astrocytes and neurons, with the exception of parvalbumin+ interneurons in the cortex. Most cell populations exhibit stable expression of LRP1 throughout development; however, the proportion of OPCs that express LRP1 increases significantly from ~69% at E15.5 to ~99% in adulthood. We also report that LRP1 expression is rapidly lost as OPCs differentiate, and is absent from all oligodendrocytes, including newborn oligodendrocytes. While LRP1 function has been primarily examined in mature neurons, these expression data suggest it plays a more critical role in glial cell regulation-where expression levels are much higher

Microglia in the brain stably express LRP1 throughout life.

<p>Coronal sections of E13.5 (a), E15.5 (c), E18 (e), P5 (g, i) and P60 (k,m) mouse brain were immunolabelled to detect microglia (Iba1, green) and LRP1 (red). The nuclear marker Hoechst 33342 was used to label cell nuclei (blue). (o) Graphical depiction of the proportion of Iba1⁺ cells that expressed LRP1. Results were compared using a one-way ANOVA with a Bonferroni’s post-hoc test, expressed as means ± std and are representative of three independent experiments. (b, d, f, h, j, l, n) secondary antibody alone controls. All images are single z plane confocal scans. White arrows indicate regions of co-localisation. Scale bars represent 17μm. Ctx = cortex, CC = corpus callosum.</p

LRP1 is developmentally unregulated by OPCs.

<p>Coronal sections of E15.5 (a), E18 (c), P5 (e,i) and P60 (k,m) mouse brain were immunolabelled to detect OPCs (PDGFRα, green) and LRP1 (red). The nuclear marker Hoechst 33342 was used to label cell nuclei (blue). (b,d,f,h,j) secondary antibody alone controls. (k) Graphical representation of the percentage of OPCs that express LRP1 in the brain at each age. Data (n = 3 mice analyzed per age) were compared using a one-way ANOVA with a Bonferroni’s post-hoc test, and expressed as mean ± std. * P<0.05, **** P<0.0001. All images are single z plane confocal scans. White arrows indicate regions of co-localisation. Scale bars represent 17μm. CC = corpus callosum, Ctx = cortex.</p

Newly formed oligodendrocytes do not express LRP1.

<p>Tamoxifen was administered to Pdgfra-CreER^T2::Rosa26-YFP transgenic mice at P57 to label OPCs and trace them as they generate new oligodendrocytes until P64. Single scan confocal images were collected through the corpus callosum (CC) following immunolabelling with YFP (green), LRP1 (red) and either PDGFRα or CC1 (blue). <b>a-a”‘</b> YFP⁺, PDGFRα⁺ cells were also LRP1⁺. <b>b-b”‘</b> YFP⁺, PDGFRα-negative cells were also negative for LRP1. <b>c-c”‘</b> YFP⁺ CC1⁺ cells were found to be LRP1-negative. White arrows indicate regions of co-localisation. Arrowheads indicate oligodendrocyte cell bodies, which do not express LRP1. Scale bars represent 17μm. CC = corpus callosum.</p

LRP1 is expressed by radial glia in the developing brain and spinal cord.

<p>Coronal sections of the E13.5 (a), E15.5 (c) and E18 (g)mouse brain and transverse sections of the E15.5 spinal cord (e) were immunolabelled to detect radial glia (RC2, green) and LRP1 (red). The nuclear marker Hoechst 33342 was used to label cell nuclei (blue). (b,d,f,h,j) secondary antibody alone controls. All images are single z plane confocal scans. White arrows indicate regions of co-localisation. Scale bars represent 17μm. SC = spinal cord.</p

LRP1 is highly expressed in the brain.

<p>Whole brain lysates from E13.5, P5 and P62 wildtype mice were analyzed by western blot to detect LRP1 (Fig 1A) and GAPDH (Fig 1A) protein expression. (c) Band pixel intensity was quantified, normalized to the loading control (GAPDH), and shows that LRP1 expression is significantly elevated in the postnatal brain compared to the embryonic (P = 0.001) and adult (P = 0.0004) brain. Results were compared using a one-way ANOVA with a Tukey’s post-hoc test, expressed as mean ± std. **P<0.01, ***P<0.001.</p

NeuN-positive neurons express LRP1, but parvalbumin-positive interneurons do not.

<p>Coronal sections through the P5 (a) and P60 (c) mouse brain, and transverse sections through the adult mouse spinal cord (e) were immunolabelled to detect mature neurons (NeuN, green) and LRP1 (red). g) Coronal section of an adult (P60) mouse brain immunolabelled to detect parvalbumin (green) and LRP1 (red). (b,d,f,h) secondary alone controls. The nuclear marker Hoechst 33342 was used to label cell nuclei (blue). All images are single z plane confocal scans. White arrows indicate regions of co-localisation. Arrow heads represent parvalbumin⁺ neurons that do not express LRP1. Scale bars represent 17μm. Ctx = cortex, SC = spinal cord.</p