Mistargeted retinal axons form synaptically segregated subcircuits in the visual thalamus of albino mice
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eLife Assessment
This study provides important morphological observations related to the potential roles of Hebbian plasticity in establishing brain connectivity, by examining synapses formed by functionally distinct groups of retinal ganglion cell (RGC) axons in albino mouse dorsolateral geniculate nucleus (dLGN). Here, inappropriately projecting contralateral RGCs undergo developmental rewiring alongside ipsilateral RGCs, such that Hebbian theory would predict them to have separate synaptic targets. The authors provide compelling support for some presence of Hebbian rewiring, using combined confocal imaging and serial electron microscopy (EM) reconstructions to show that contralateral RGCs form completely segregated synaptic inputs onto islands of dLGN thalamocortical neurons, as well as somewhat segregated synaptic input onto local inhibitory interneurons. These findings will be of interest to researchers studying synaptic connectivity and plasticity during development.
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Abstract
A Hebbian model of circuit remodeling predicts that two sets of inputs with sufficiently distinct activity patterns will synaptically capture separate sets of target cells. Mice in which a subset of retinal ganglion cells (RGCs) target the wrong region of the dorsal lateral geniculate nucleus (dLGN) provide the conditions for testing this prediction. In albino mice, mistargeted RGC axons form an island of terminals that is distinct from the surrounding neuropil. Blocking retinal activity during development prevents the formation of this island. However, the synaptic connectivity of the island was unknown. Here, we combine light and electron microscopy to determine if this activity-dependent island of axon terminals represent a synaptically segregated subcircuit. We reconstructed the microcircuitry of the boundary between the island and non-island RGCs and found a remarkably strong segregation within retinogeniculate connectivity. We conclude that, when sets of retinal input are established in the wrong part of the dLGN, the developing circuitry responds by forming a synaptically isolated subcircuit from the otherwise fully connected network. The fact that there is a developmental starting condition that can induce a synaptically segregated microcircuit has important implications for our understanding of the organization of visual circuits and for our understanding of the implementation of activity dependent development.
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eLife Assessment
This study provides important morphological observations related to the potential roles of Hebbian plasticity in establishing brain connectivity, by examining synapses formed by functionally distinct groups of retinal ganglion cell (RGC) axons in albino mouse dorsolateral geniculate nucleus (dLGN). Here, inappropriately projecting contralateral RGCs undergo developmental rewiring alongside ipsilateral RGCs, such that Hebbian theory would predict them to have separate synaptic targets. The authors provide compelling support for some presence of Hebbian rewiring, using combined confocal imaging and serial electron microscopy (EM) reconstructions to show that contralateral RGCs form completely segregated synaptic inputs onto islands of dLGN thalamocortical neurons, as well as somewhat segregated synaptic input onto local …
eLife Assessment
This study provides important morphological observations related to the potential roles of Hebbian plasticity in establishing brain connectivity, by examining synapses formed by functionally distinct groups of retinal ganglion cell (RGC) axons in albino mouse dorsolateral geniculate nucleus (dLGN). Here, inappropriately projecting contralateral RGCs undergo developmental rewiring alongside ipsilateral RGCs, such that Hebbian theory would predict them to have separate synaptic targets. The authors provide compelling support for some presence of Hebbian rewiring, using combined confocal imaging and serial electron microscopy (EM) reconstructions to show that contralateral RGCs form completely segregated synaptic inputs onto islands of dLGN thalamocortical neurons, as well as somewhat segregated synaptic input onto local inhibitory interneurons. These findings will be of interest to researchers studying synaptic connectivity and plasticity during development.
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Reviewer #1 (Public review):
Summary:
The authors examined whether aberrantly projecting retinal ganglion cells in albino mice innervate a separate population of thalamocortical neurons, as would be predicted for Hebbian learning rules. The authors find support for this hypothesis in correlated light and electron microscopy (CLEM) reconstructions of retinal ganglion cell axons and thalamocortical neurons. In a second line of investigation, the authors ask the same question about retinal ganglion cell innervation of local inhibitory interneurons of the mouse LGN. The authors conclude that these connections are less specific.
Strengths:
The authors make good use of CLEM to test a circuit-level hypothesis, and they find an interesting difference in RGC synaptic innervation patterns for thalamocortical neurons vs. local interneurons.
Weaknes…
Reviewer #1 (Public review):
Summary:
The authors examined whether aberrantly projecting retinal ganglion cells in albino mice innervate a separate population of thalamocortical neurons, as would be predicted for Hebbian learning rules. The authors find support for this hypothesis in correlated light and electron microscopy (CLEM) reconstructions of retinal ganglion cell axons and thalamocortical neurons. In a second line of investigation, the authors ask the same question about retinal ganglion cell innervation of local inhibitory interneurons of the mouse LGN. The authors conclude that these connections are less specific.
Strengths:
The authors make good use of CLEM to test a circuit-level hypothesis, and they find an interesting difference in RGC synaptic innervation patterns for thalamocortical neurons vs. local interneurons.
Weaknesses:
The conclusions about the local interneuron innervation are a little more difficult to interpret. One would expect to only capture a small part of the local interneuron dendritic field, as compared to the smaller thalamocortical neurons, right? Doesn't that imply that finding some evidence of promiscuous connectivity means that other dendrites that were not observed probably connect to many different RGCs?
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Reviewer #2 (Public review):
In this article, the authors examined the organization of misplaced retinal inputs in the visual thalamus of albino mice at electron-microscopic (EM) resolution to determine whether these synaptic inputs are segregated from the rest of the retinogeniculate circuitry.
The study's major strengths include its high resolution, achieved through serial EM and confocal microscopy, which enabled the identification of all synaptic inputs onto neurons in the dorsolateral geniculate nucleus (dLGN).
The experiments are very precise and demanding; thus, only the synaptic inputs of a few neurons were fully reconstructed in one animal. A few figures could be improved in their presentation.
Despite this, the authors clearly demonstrate the synaptic segregation of misrouted retinal axons onto dLGN neurons, separate from the …
Reviewer #2 (Public review):
In this article, the authors examined the organization of misplaced retinal inputs in the visual thalamus of albino mice at electron-microscopic (EM) resolution to determine whether these synaptic inputs are segregated from the rest of the retinogeniculate circuitry.
The study's major strengths include its high resolution, achieved through serial EM and confocal microscopy, which enabled the identification of all synaptic inputs onto neurons in the dorsolateral geniculate nucleus (dLGN).
The experiments are very precise and demanding; thus, only the synaptic inputs of a few neurons were fully reconstructed in one animal. A few figures could be improved in their presentation.
Despite this, the authors clearly demonstrate the synaptic segregation of misrouted retinal axons onto dLGN neurons, separate from the rest of the retinogeniculate circuitry.
This finding is impactful because retinal inputs typically do not segregate within the mouse dLGN, and it was previously thought that this was due to the nucleus's small size, which might prevent proper segregation. The study shows that in cases where axons are misrouted and exhibit a different activity pattern than surrounding retinal inputs, segregation of inputs can indeed occur. This suggests that the normal system has the capacity to segregate inputs, despite the limited volume of the mouse dLGN.
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