Postsynaptic and Presynaptic NMDARs Have Distinct Roles in Visual Circuit Development

Kesner, Philip; Schohl, Anne; Warren, Elodie C.; Ruthazer, Edward S.

doi:10.1016/j.celrep.2020.107955

Cited by 17 publications

(31 citation statements)

References 73 publications

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“…In the SC of pre-cKO mice, we did not observe alterations in the size of TZs from labeled RGCs, demonstrating that NMDARs expressed by these neurons are not required for topographic refinement in this region. Interestingly, these data are somewhat inconsistent with recent work in which sparser retinotectal terminals were observed when GluN1 expression was knocked down specifically in RGCs ( Kesner et al, 2020 ). However, the total size of the terminal arbor may have been less dramatically impacted, as no change was observed in total terminal branch length.…”

Section: Discussioncontrasting

confidence: 95%

“…This result is consistent with previous studies leveraging pharmacologic NMDAR blockade, in which disruptions of RGC axonal arbor dynamics were observed (Rajan et al, 1999;Ruthazer et al, 2003;Munz et al, 2014), but the overall mature organization of arborizations was not dramatically altered (Cline & Constantine-Paton, 1989). Indeed, functional analyses revealed no changes in overall receptive field size when GluN1 expression was knocked down in RGCs, consistent with minimal change in topography (Kesner et al, 2020). One possible reason for a lack of phenotype in terms of topographic refinement may be that the Cre line chosen is expressed in only ~65% of RGCs (Drayson & Triplett, 2019).…”

Section: Nmdars Expressed By Rgcs Are Not Required For Retinotopysupporting

confidence: 92%

“…Thus far, our data suggest that retinofugal development is not dependent on NMDAR expression in RGCs. One possibility for this could be that pre-synaptic NMDARs may not be located in the terminals of RGCs in these retinorecipient centers, contrary to what has been suggested in the frog tectum (Kesner et al, 2020). To test this, we crossed the Chrnb3-Cre line with Cre-dependent GCaMP5G::tdTom reporter mice (Gee et al, 2014) and performed Ca 2+ imaging in retinorecipient areas, where only RGC terminals would be labeled.…”

Section: Activation Of Nmda-mediated Response In Rgc Terminals In Retinorecipient Areasmentioning

confidence: 97%

“…Previous studies suggest that developing RGCs express NMDARs raising the possibility they could be localized presynaptically in retinorecipient regions ( Massey and Miller, 1990 ; Mittman et al, 1990 ; Watanabe et al, 1994 ). Indeed, recent work demonstrated that presynaptic and postsynaptic NMDARs have distinct but complementary roles in developmental plasticity in the retinotectal system ( Kesner et al, 2020 ). However, whether NMDARs expressed by RGCs are required for topographic refinement remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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NMDA Receptor Expression by Retinal Ganglion Cells Is Not Required for Retinofugal Map Formation nor Eye-Specific Segregation in the Mouse

Johnson

Smith

Goldstein³

et al. 2021

eNeuro

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Retinal ganglion cells (RGCs) project topographically to the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). Spontaneous activity plays a critical role in retinotopic mapping in both regions; however, the molecular mechanisms underlying activity-dependent refinement remain unclear. Previous pharmacologic studies implicate NMDA receptors (NMDARs) in the establishment of retinotopy. In other brain regions, NMDARs are expressed on both the pre-and post-synaptic side of the synapse, and recent work suggests that pre-synaptic and post-synaptic NMDARs play distinct roles in retinotectal developmental dynamics. To directly test the role of NMDARs expressed by RGCs in retinofugal map formation, we took a conditional genetic knockout approach to delete the obligate GluN1 subunit of NMDARs in RGCs. Here, we demonstrate reduced GluN1 expression in the retina of Chrnb3-Cre;GluN1 flox/flox (pre-cKO) mice without altered expression in the SC. Anatomical tracing experiments revealed no significant changes in termination zone size in the SC and dLGN of pre-cKO mice, suggesting NMDAR function in RGCs is not an absolute requirement for topographic refinement. Further, we observed no change in the eye-specific organization of retinal inputs to the SC nor dLGN. To verify that NMDA induces activity in RGC terminals, we restricted GCaMP5 expression to RGCs and confirmed induction of calcium transients in RGC terminals. Together, these findings demonstrate that NMDARs expressed by RGCs are not required for retinofugal topographic map formation nor eye-specific segregation in the mouse. 4 Significance StatementTopographic organization of retinal inputs in the brain is thought to be critical for the efficient relay of spatial information in the visual scene. Previous studies suggest NMDARs play a crucial role in establishing topography in the superior colliculus; however, these studies could not distinguish between potential pre-or post-synaptic roles. Here, we show NMDAR function in retinal ganglion cells (RGCs) is not required for the establishment of topography. Further, we find RGC NMDARs are not required to establish or maintain eye-specific laminae in retinorecipient regions.

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Section: Discussioncontrasting

confidence: 95%

Section: Nmdars Expressed By Rgcs Are Not Required For Retinotopysupporting

confidence: 92%

Section: Activation Of Nmda-mediated Response In Rgc Terminals In Retinorecipient Areasmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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NMDA Receptor Expression by Retinal Ganglion Cells Is Not Required for Retinofugal Map Formation nor Eye-Specific Segregation in the Mouse

Johnson

Smith

Goldstein³

et al. 2021

eNeuro

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“…4 and Videos 6-9). Previous research in our lab has demonstrated that NMDARs are not present on radial astrocytes during these developmental stages 34,40 , so we focused on AMPARs and mGluRs, specifically mGluR1 and mGluR5 given the weight of the literature suggesting a role for these type-1 mGluRs during early development 16 . Compared to control treatment, AMPA (100 μM) in animals pretreated with TTX (1 μM) did not significantly increase the number of active glia but did increase the number of active neurons, while the mGluR1/5 agonist DHPG (200μM) showed a non-significant increase in the number of active glia and a significant increase in the number of active neurons.…”

Section: Resultsmentioning

confidence: 99%

Sodium-Calcium Exchanger Mediates Sensory-Evoked Glial Calcium Transients in the Developing Retinotectal System

Benfey

Schohl

et al. 2020

Preprint

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Various types of sensory stimuli have been shown to induce calcium elevations in glia. However, a mechanistic understanding of the signalling pathways mediating sensory-evoked activity in glia in intact animals is still emerging. Here we demonstrate that during early development of the Xenopus laevis visual system, radial astrocytes in the optic tectum are highly responsive to sensory stimulation. Calcium transients occur spontaneously in radial astrocytes at rest and are abolished by silencing neuronal activity with tetrodotoxin. Visual stimulation drives temporally correlated increases in the activity patterns of neighbouring radial astrocytes. Following blockade of all glutamate receptors, visually-evoked calcium activity in radial astrocytes is enhanced, rather than suppressed, while the additional blockade of either glutamate transporters or sodium-calcium exchangers (NCX) fully prevents visually-evoked responses. Additionally, we demonstrate that blockade of NCX alone is sufficient to prevent visually-evoked responses in radial astrocytes, highlighting a pivotal role for NCX in glia during development.

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Activity‐dependent alteration of early myelin ensheathment in a developing sensory circuit

Chorghay

MacFarquhar

et al. 2021

J of Comparative Neurology

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Myelination allows for the regulation of conduction velocity, affecting the precise timing of neuronal inputs important for the development and function of brain circuits. In turn, myelination may be altered by changes in experience, neuronal activity, and vesicular release, but the links between sensory experience, corresponding neuronal activity, and resulting alterations in myelination require further investigation. We thus studied the development of myelination in the Xenopus laevis tadpole, a classic model for studies of visual system development and function because it is translucent and visually responsive throughout the formation of its retinotectal system. We begin with a systematic characterization of the timecourse of early myelin ensheathment in the Xenopus retinotectal system using immunohistochemistry of myelin basic protein (MBP) along with third harmonic generation (THG) microscopy, a label-free structural imaging technique. Based on the mid-larval developmental progression of MBP expression in Xenopus, we identified an appropriate developmental window in which to assess the effects of early temporally patterned visual experience on myelin ensheathment. We used calcium imaging of axon terminals in vivo to characterize the responses of retinal ganglion cells over a range of stroboscopic stimulation frequencies. Strobe frequencies that reliably elicited robust versus dampened calcium responses were then presented to animals for 7 d, and differences in the amount of early myelin ensheathment at the optic chiasm were subsequently quantified. This study provides evidence that it is not just the presence but also to the specific temporal properties of sensory stimuli that are important for myelin plasticity.

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Postsynaptic and Presynaptic NMDARs Have Distinct Roles in Visual Circuit Development

Cited by 17 publications

References 73 publications

NMDA Receptor Expression by Retinal Ganglion Cells Is Not Required for Retinofugal Map Formation nor Eye-Specific Segregation in the Mouse

NMDA Receptor Expression by Retinal Ganglion Cells Is Not Required for Retinofugal Map Formation nor Eye-Specific Segregation in the Mouse

Sodium-Calcium Exchanger Mediates Sensory-Evoked Glial Calcium Transients in the Developing Retinotectal System

Activity‐dependent alteration of early myelin ensheathment in a developing sensory circuit

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