Developmental oligodendrocytes regulate brain function through the mediation of synchronized spontaneous activity
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eLife Assessment
In this valuable manuscript, authors ablate cerebellar oligodendrocytes during postnatal development and show that synchrony of calcium transients in Purkinje neurons and behaviours are affected even at later stages. While the work is solid, it is incomplete in that the causal relationship between the two has not been sufficiently explored.
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Abstract
Synchronized spontaneous neural activity is a fundamental feature of developing central nervous systems, hypothesized to be critical for brain development. However, the mechanisms regulating this synchronization and its long-term functional implications remain poorly understood. Here, we unveil a novel role for oligodendrocytes in orchestrating synchronized spontaneous activity during a critical developmental window, with profound consequences for adult brain function. Using cell-specific genetic manipulation in the mouse cerebellum, we demonstrate that oligodendrocyte deficiency during early postnatal development, but not after weaning, disrupts the synchronization of Purkinje cell activity in both developmental and adult stages. These early disruption of oligodendrocytes and neural synchrony resulted in persistent alterations in adult cerebellar-dependent behaviors, including anxiety, sociality, and motor function. Our findings establish a causal link between developmental oligodendrocyte-regulated neural synchrony and the emergence of complex brain functions. This study ensures the proper developmental trajectory necessary for driving brain function and opens new avenues for understanding neurodevelopmental disorders.
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eLife Assessment
In this valuable manuscript, authors ablate cerebellar oligodendrocytes during postnatal development and show that synchrony of calcium transients in Purkinje neurons and behaviours are affected even at later stages. While the work is solid, it is incomplete in that the causal relationship between the two has not been sufficiently explored.
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Reviewer #1 (Public review):
Summary:
This study presents convincing findings that oligodendrocytes play a regulatory role in spontaneous neural activity synchronisation during early postnatal development, with implications for adult brain function. Utilising targeted genetic approaches, the authors demonstrate how oligodendrocyte depletion impacts Purkinje cell activity and behaviours dependent on cerebellar function. Delayed myelination during critical developmental windows is linked to persistent alterations in neural circuit function, underscoring the lasting impact of oligodendrocyte activity.
Strengths:
(1) The research leverages the anatomically distinct olivocerebellar circuit, a well-characterized system with known developmental timelines and inputs, strengthening the link between oligodendrocyte function and neural …
Reviewer #1 (Public review):
Summary:
This study presents convincing findings that oligodendrocytes play a regulatory role in spontaneous neural activity synchronisation during early postnatal development, with implications for adult brain function. Utilising targeted genetic approaches, the authors demonstrate how oligodendrocyte depletion impacts Purkinje cell activity and behaviours dependent on cerebellar function. Delayed myelination during critical developmental windows is linked to persistent alterations in neural circuit function, underscoring the lasting impact of oligodendrocyte activity.
Strengths:
(1) The research leverages the anatomically distinct olivocerebellar circuit, a well-characterized system with known developmental timelines and inputs, strengthening the link between oligodendrocyte function and neural synchronization.
(2) Functional assessments, supported by behavioral tests, validate the findings of in vivo calcium imaging, enhancing the study's credibility.
(3) Extending the study to assess the long-term effects of early-life myelination disruptions adds depth to the implications for both circuit function and behavior.
Weaknesses:
(1) The study would benefit from a closer analysis of myelination during the periods when synchrony is recorded. Direct correlations between myelination and synchronized activity would substantiate the mechanistic link and clarify if observed behavioral deficits stem from altered myelination timing.
(2) Although the study focuses on Purkinje cells in the cerebellum, neural synchrony typically involves cross-regional interactions. Expanding the discussion on how localized Purkinje synchrony affects broader behaviors - such as anxiety, motor function, and sociality - would enhance the findings' functional significance.
(3) The authors discuss the possibility of oligodendrocyte-mediated synapse elimination as a possible mechanism behind their findings, drawing from relevant recent literature on oligodendrocyte precursor cells. However, there are no data presented supporting this assumption. The authors should explain why they think the mechanism behind their observation extends beyond the contribution of myelination or remove this point from the discussion entirely.
(4) It would be valuable to investigate the secondary effects of oligodendrocyte depletion on other glial cells, particularly astrocytes or microglia, which could influence long-term behavioral outcomes. Identifying whether the lasting effects stem from developmental oligodendrocyte function alone or also involve myelination could deepen the study's insights.
(5) The authors should explore the use of different methods to disturb myelin production for a longer time, in order to further determine if the observed effects are transient or if they could have longer-lasting effects.
(6) Throughout the paper, there are concerns about statistical analyses, particularly on the use of the Mann-Whitney test or using fields of view as biological replicates.
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Reviewer #2 (Public review):
Summary:
In this manuscript, the authors use genetic tools to ablate oligodendrocytes in the cerebellum during postnatal development. They show that the oligodendrocyte numbers return to normal post-weaning. Yet, the loss of oligodendrocytes during development seems to result in decreased synchrony of calcium transients in Purkinje neurons across the cerebellum. Further, there were deficits in social behaviors and motor coordination. Finally, they suppress activity in a subset of climbing fibers to show that it results in similar phenotypes in the calcium signaling and behavioral assays. They conclude that the behavioral deficits in the oligodendrocyte ablation experiments must result from loss of synchrony.
Strengths:
Use of genetic tools to induce perturbations in a spatiotemporally specific manner.
Weaknes…
Reviewer #2 (Public review):
Summary:
In this manuscript, the authors use genetic tools to ablate oligodendrocytes in the cerebellum during postnatal development. They show that the oligodendrocyte numbers return to normal post-weaning. Yet, the loss of oligodendrocytes during development seems to result in decreased synchrony of calcium transients in Purkinje neurons across the cerebellum. Further, there were deficits in social behaviors and motor coordination. Finally, they suppress activity in a subset of climbing fibers to show that it results in similar phenotypes in the calcium signaling and behavioral assays. They conclude that the behavioral deficits in the oligodendrocyte ablation experiments must result from loss of synchrony.
Strengths:
Use of genetic tools to induce perturbations in a spatiotemporally specific manner.
Weaknesses:
The main weakness in this manuscript is the lack of a cohesive causal connection between the experimental manipulation performed and the phenotypes observed. Though they have taken great care to induce oligodendrocyte loss specifically in the cerebellum and at specific time windows, the subsequent experiments do not address specific questions regarding the effect of this manipulation. Calcium transients in Purkinje neurons are caused to a large extent by climbing fibers, but there is evidence for simple spikes to also underlie the dF/F signatures (Ramirez and Stell, Cell Reports, 2016). Also, it is erroneous to categorize these calcium signals as signatures of "spontaneous activity" of Purkinje neurons as they can have dual origins. Further, the effect of developmental oligodendrocyte ablation on the cerebellum has been previously reported by Mathis et al., Development, 2003. They report very severe effects such as the loss of molecular layer interneurons, stunted Purkinje neuron dendritic arbors, abnormal foliations, etc. In this context, it is hardly surprising that one would observe a reduction of synchrony in Purkinje neurons (perhaps due to loss of synaptic contacts, not only from CFs but also from granule cells). The last experiment with the expression of Kir2.1 in the inferior olive is hardly convincing. In summary, while the authors used a specific tool to probe the role of developmental oligodendrocytes in cerebellar physiology and function, they failed to answer specific questions regarding this role, which they could have done with more fine-grained experimental analysis.
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