GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury

Zonouzi, Marzieh; Scafidi, Joseph; Li, Peijun; McEllin, Brian; Edwards, Jorge; Dupree, Jeffrey L.; Harvey, Lloyd D.; Sun, Dandan; Hübner, Christian A.; Cull-Candy, SG; Farrant, M; Gallo, Vittorio

doi:10.1038/nn.3990

Cited by 179 publications

(247 citation statements)

References 70 publications

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“…Studies in which the proliferative marker Ki67 was employed, suggest that the proliferative capacity of NG2 glia is generally low. In the white matter of the cerebellum, immunoreactivity for Ki67 was below 10 % at P7 and basically absent in adults (Zonouzi et al 2015). A comparably low proliferative capacity was reported in the murine optic nerve (Solga et al 2014).…”

Section: Introductionmentioning

confidence: 83%

Changes in the proliferative capacity of NG2 cell subpopulations during postnatal development of the mouse hippocampus

et al. 2016

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Besides astrocytes and oligodendrocytes, NG2 proteoglycan-expressing cells (NG2 glia) represent a third subtype of macroglia in the brain. Originally described as oligodendrocyte precursor cells, they feature several characteristics not expected from mere progenitor cells, including synaptic connections with neurons. There is accumulating evidence that the properties of NG2 glia differ between different brain regions and developmental stages. To further analyze this proposed heterogeneity, we studied electrophysiological properties, transcript and protein expression, distribution and proliferative capacity of NG2 glia during postnatal development, focusing on the hippocampus and corpus callosum. All NG2 glia displayed a 'complex' current pattern consisting of voltage- and time-dependent in- and outward currents. In juvenile mice, Kir current densities and rectification index were highly variable and on average significantly lower than in adult animals. Single cell RT-PCR analyses of electrophysiologically characterized cells demonstrated that different glial genes were expressed at variable extent, independent of developmental stage and genetic background. In the hippocampus proper and the corpus callosum, the density of NG2 glia was highest at postnatal days (P)10-12, decreased by ~50 % at P25-35 and then remained stable in adults (P80-90). Interestingly, co-expression of NG2 and S100β, a marker for mature astrocytes, increased from 7 % at P10-12 to 27 % at P25-35 in the hippocampus proper, and then dropped again in the stratum radiatum at P80-90. In the dentate gyrus and corpus callosum, co-expression of NG2 and S100β was very low (3 %) and constant throughout development. Age-related differences were also observed with Ki-67, a proliferation marker. In NG2 glia of the CA1 region, its expression decreased from 16 % at P10-12 to 9 % (P25-35) and then 3 % (P80-90). Triple-stainings revealed that Ki-67 was also expressed in 2-3 % of NG2/S100β-positive cells in the juvenile and mature stratum radiatum, indicating that the latter, in contrast to S100β-positive astrocytes, still host proliferative potential. Taken together, we found significant differences in transcript and protein expression, electrophysiological properties and proliferative capacity of NG2 glia in the mouse forebrain, suggesting the co-existence of several subpopulations of NG2 glia. Our data thus support the idea of a substantial regional and developmental heterogeneity in this subtype of macroglia.

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Section: Introductionmentioning

confidence: 83%

Changes in the proliferative capacity of NG2 cell subpopulations during postnatal development of the mouse hippocampus

et al. 2016

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“…Conversely, chronic activation of GABA A receptors with GABA or their blockade by either Zn 21 or bicuculline in cerebellar organotypic cultures did not alter MBP expression levels (data not shown). Nevertheless, GABA A receptors in OLGs and their precursors may be crucial for proper myelination and remyelination after injury since disruption of GABAergic communication in NG2-expressing progenitor cells during cerebellar development results in a delay of OLG maturation and dysmyelination (Zonouzi et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…They probably act as paracrine or autocrine signals in addition to their role in synaptic transmission, and they have diverse effects in either stimulating or regulating specific membrane receptors expressed in the OPC and OLG membrane (Káradóttir and Attwell, 2007;Boulanger and Messier 2014). Thus, adenosine, glutamate, GABA, and ATP can modulate the proliferation, differentiation, and migration of OPC as well as OLG survival and myelination (e.g., Gallo et al, 1996;Gudz et al, 2006;Ishibashi et al, 2006;Domercq et al, 2010;Etxeberria et al, 2010;Wake et al, 2011;Zonouzi et al, 2015). In particular, both OPCs and mature OLGs express the two main subtypes of GABA receptors: GABA A (Hoppe and Kettenmann 1989;Von Blankenfeld et al, 1991;Berger et al, 1992;Cahoy et al, 2008) and GABA B (Luyt et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, both OPCs and mature OLGs express the two main subtypes of GABA receptors: GABA A (Hoppe and Kettenmann 1989;Von Blankenfeld et al, 1991;Berger et al, 1992;Cahoy et al, 2008) and GABA B (Luyt et al, 2007). Sensitivity to GABA in mature OLGs is greatly reduced (Berger et al, 1992), which suggests a specific role for GABA signaling in the development of the oligodendroglial lineage and during the initial stages of myelination and/or axon recognition (Vélez-Fort et al, 2012;Zonouzi et al, 2015). However, there is no detailed information about the status and fate of the different receptors and channels in this specific time window when OLGs encounter axons.…”

Section: Introductionmentioning

confidence: 99%

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Axon-to-Glia Interaction Regulates GABA_AReceptor Expression in Oligodendrocytes

Arellano¹,

Sánchez‐Gómez²,

Alberdi³

et al. 2015

Mol Pharmacol

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Myelination requires oligodendrocyte-neuron communication, and both neurotransmitters and contact interactions are essential for this process. Oligodendrocytes are endowed with neurotransmitter receptors whose expression levels and properties may change during myelination. However, only scant information is available about the extent and timing of these changes or how they are regulated by oligodendrocyte-neuron interactions. Here, we used electrophysiology to study the expression of ionotropic GABA, glutamate, and ATP receptors in oligodendrocytes derived from the optic nerve and forebrain cultured either alone or in the presence of dorsal root ganglion neurons. We observed that oligodendrocytes from both regions responded to these transmitters at 1 day in culture. After the first day in culture, however, GABA sensitivity diminished drastically to less than 10%, while that of glutamate and ATP remained constant. In contrast, the GABA response amplitude was sustained and remained stable in oligodendrocytes cocultured with dorsal root ganglion neurons. Immunochemistry and pharmacological properties of the responses indicated that they were mediated by distinctive GABA A receptors and that in coculture with neurons, the oligodendrocytes bearing the receptors were those in direct contact with axons. These results reveal that GABA A receptor regulation in oligodendrocytes is driven by axonal cues and that GABA signaling may play a role in myelination and/or during axonglia recognition.

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“…Traumatic brain injury, often observed in athletes and soldiers, also can cause dendritic damage (Gao et al 2011;Xiong et al 2013). Perinatal hypoxia causes simplification of Purkinje neuron dendrites in mice (Zonouzi et al 2015). Defects in dendrite morphology and electrophysiology are observed early in mouse models of Huntington's disease, after behavioral symptom onset but before neurodegenerative cell death begins (Klapstein et al 2001).…”

mentioning

confidence: 99%

In vivo dendrite regeneration after injury is different from dendrite development

Thompson-Peer

DeVault

et al. 2016

Genes Dev.

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Neurons receive information along dendrites and send signals along axons to synaptic contacts. The factors that control axon regeneration have been examined in many systems, but dendrite regeneration has been largely unexplored. Here we report that, in intact Drosophila larvae, a discrete injury that removes all dendrites induces robust dendritic growth that recreates many features of uninjured dendrites, including the number of dendrite branches that regenerate and responsiveness to sensory stimuli. However, the growth and patterning of injury-induced dendrites is significantly different from uninjured dendrites. We found that regenerated arbors cover much less territory than uninjured neurons, fail to avoid crossing over other branches from the same neuron, respond less strongly to mechanical stimuli, and are pruned precociously. Finally, silencing the electrical activity of the neurons specifically blocks injury-induced, but not developmental, dendrite growth. By elucidating the essential features of dendrites grown in response to acute injury, our work builds a framework for exploring dendrite regeneration in physiological and pathological conditions.

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GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury

Cited by 179 publications

References 70 publications

Changes in the proliferative capacity of NG2 cell subpopulations during postnatal development of the mouse hippocampus

Changes in the proliferative capacity of NG2 cell subpopulations during postnatal development of the mouse hippocampus

Axon-to-Glia Interaction Regulates GABA_AReceptor Expression in Oligodendrocytes

In vivo dendrite regeneration after injury is different from dendrite development

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GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury

Cited by 179 publications

References 70 publications

Changes in the proliferative capacity of NG2 cell subpopulations during postnatal development of the mouse hippocampus

Changes in the proliferative capacity of NG2 cell subpopulations during postnatal development of the mouse hippocampus

Axon-to-Glia Interaction Regulates GABAAReceptor Expression in Oligodendrocytes

In vivo dendrite regeneration after injury is different from dendrite development

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Axon-to-Glia Interaction Regulates GABA_AReceptor Expression in Oligodendrocytes