Retinogeniculate Axons Research Articles

Semaphorin-6D and Plexin-A1 Act in a Non-Cell-Autonomous Manner to Position and Target Retinal Ganglion Cell Axons.

Semaphorins and Plexins form ligand/receptor pairs that are crucial for a wide range of developmental processes from cell proliferation to axon guidance. The ability of semaphorins to act both as signaling receptors and ligands yields a multitude of responses. Here, we describe a novel role for Semaphorin-6D (Sema6D) and Plexin-A1 in the positioning and targeting of retinogeniculate axons. In Plexin-A1 or Sema6D mutant mice of either sex, the optic tract courses through, rather than along, the border of the dorsal lateral geniculate nucleus (dLGN), and some retinal axons ectopically arborize adjacent and lateral to the optic tract rather than defasciculating and entering the target region. We find that Sema6D and Plexin-A1 act together in a dose-dependent manner, as the number of the ectopic retinal projections is altered in proportion to the level of Sema6D or Plexin-A1 expression. Moreover, using retinal in utero electroporation of Sema6D or Plexin-A1 shRNA, we show that Sema6D and Plexin-A1 are both required in retinal ganglion cells for axon positioning and targeting. Strikingly, nonelectroporated retinal ganglion cell axons also mistarget in the tract region, indicating that Sema6D and Plexin-A1 can act non-cell-autonomously, potentially through axon-axon interactions. These data provide novel evidence for a dose-dependent and non-cell-autonomous role for Sema6D and Plexin-A1 in retinal axon organization in the optic tract and dLGN.SIGNIFICANCE STATEMENT Before innervating their central brain targets, retinal ganglion cell axons fasciculate in the optic tract and then branch and arborize in their target areas. Upon deletion of the guidance molecules Plexin-A1 or Semaphorin-6D, the optic tract becomes disorganized near and extends within the dorsal lateral geniculate nucleus. In addition, some retinal axons form ectopic aggregates within the defasciculated tract. Sema6D and Plexin-A1 act together as a receptor-ligand pair in a dose-dependent manner, and non-cell-autonomously, to produce this developmental aberration. Such a phenotype highlights an underappreciated role for axon guidance molecules in tract cohesion and appropriate defasciculation near, and arborization within, targets.

Adaptive Reorganization in Retinogeniculate Axon Terminals Provides Substrate for Visual Recovery Following Mild TBI in Rodents

Online date: November 16, 2020 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Maternal immune activation alters visual acuity and retinogeniculate axon pruning in offspring mice

Individuals with autism spectrum disorder (ASD) have been found to have a variety of sensory processing deficits. Here we report that maternal immune activation, a known factor for ASD, alters visual acuity in the offspring mice. By intraperitoneally injecting polyinosinic-polycytidylic acid (polyI:C) to induce maternal immune activation during embryonic days 10 to 14, we found that polyI:C treatment impairs visual acuity in young adult offspring mice as examined by their optomotor responses. Concurrently, polyI:C treatment suppresses retinogeniculate axon elimination, resulting in a high fraction of weak optical fibers innervating the relay neurons in the visual thalamus. The results link in-utero maternal inflammation to defective optical fiber pruning and arrested developmental strengthening of single optic fibers which may underlie impaired visual acuity.

The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development.

Complement-mediated synapse elimination has emerged as an important process in both brain development and neurological diseases, but whether neurons express complement inhibitors that protect synapses against complement-mediated synapse elimination remains unknown. Here, we show that the sushi domain protein SRPX2 is a neuronally expressed complement inhibitor that regulates complement-dependent synapse elimination. SRPX2 directly binds to C1q and blocks its activity, and SRPX2−/Y mice show increased C3 deposition and microglial synapse engulfment. They also show a transient decrease in synapse numbers and increase in retinogeniculate axon segregation in the lateral geniculate nucleus. In the somatosensory cortex, SRPX2−/Y mice show decreased thalamocortical synapse numbers and increased spine pruning. Dual C3−/−;SRPX2−/Y mice exhibit phenotypes associated with C3−/− mice rather than SRPX2−/Y mice, indicating that C3 is necessary for SRPX2’s effect on synapse elimination. Together, these results show that SRPX2 protects synapses against complement-mediated elimination in both the thalamus and the cortex.

Environmental Enrichment Rescues Visually-Mediated Behavior in Ten-m3 Knockout Mice During an Early Critical Period.

Environmental enrichment (EE) has been shown to promote neural plasticity. Its capacity to induce functional repair in models which exhibit profound sensory deficits due to aberrant axonal guidance has not been well-characterized. Ten-m3 knockout (KO) mice exhibit a highly-stereotyped miswiring of ipsilateral retinogeniculate axons and associated profound deficits in binocularly-mediated visual behavior. We determined whether, and when, EE can drive functional recovery by analyzing Ten-m3 KO and wildtype (WT) mice that were enriched for 6 weeks from adulthood, weaning or birth in comparison to standard-housed controls. EE initiated from birth, but not later, rescued the response of Ten-m3 KOs to the “looming” stimulus (expanding disc in dorsal visual field), suggesting improved visual function. EE can thus induce recovery of visual behavior, but only during an early developmentally-restricted time-window.

Environmental Enrichment Partially Repairs Subcortical Mapping Errors in Ten-m3 Knock-Out Mice during an Early Critical Period.

Environmental enrichment (EE) has been shown to improve neural function via the regulation of cortical plasticity. Its capacity to induce functional and/or anatomical repair of miswired circuits is unknown. Ten-m3 knock-out (KO) mice exhibit a highly stereotyped and profound miswiring of ipsilateral retinogeniculate axons and associated deficits in binocularly-mediated visual behavior. We determined whether, and when, EE can drive the repair of subcortical wiring deficits by analyzing Ten-m3 KO and wild-type (WT) mice that were enriched for six weeks from adulthood, weaning or birth in comparison to standard-housed (SE) controls. Six weeks of EE initiated from birth, but not later, induced a significant reduction in the area occupied by ipsilateral retinogeniculate terminals in KOs. No EE-induced correction of mistargeted axons was observed at postnatal day (P)7, indicating that this intervention impacts pruning rather than initial targeting of axons. This reduction was most prominent in the ventrolateral region of the dorsal lateral geniculate nucleus (dLGN), suggesting a preferential pruning of the most profoundly mistargeted axons. EE can thus partially repair a specific, subcortical axonal wiring deficit, but only during an early, developmentally-restricted time window.

Adaptive reorganization of retinogeniculate axon terminals in dorsal lateral geniculate nucleus following experimental mild traumatic brain injury

The pathologic process in traumatic brain injury marked by delayed axonal loss, known as diffuse axonal injury (DAI), leads to partial deafferentation of neurons downstream of injured axons. This process is linked to persistent visual dysfunction following mild traumatic brain injury (mTBI), however, examination of deafferentation in humans is impossible with current technology. To investigate potential reorganization in the visual system following mTBI, we utilized the central fluid percussion injury (cFPI) mouse model of mTBI. We report that in the optic nerve of adult male C57BL/6J mice, axonal projections of retinal ganglion cells (RGCs) to their downstream thalamic target, dorsal lateral geniculate nucleus (dLGN), undergo DAI followed by scattered, widespread axon terminals loss within the dLGN at 4days post-injury. However, at 10days post-injury, significant reorganization of RGC axon terminals was found, suggestive of an adaptive neuroplastic response. While these changes persisted at 20days post-injury, the RGC axon terminal distribution did not recovery fully to sham-injury levels. Our studies also revealed that following DAI, the segregation of axon terminals from ipsilateral and contralateral eye projections remained consistent with normal adult mouse distribution. Lastly, our examination of the shell and core of dLGN suggested that different RGC subpopulations may vary in their susceptibility to injury or in their contribution to reorganization following injury. Collectively, these findings support the premise that subcortical axon terminal reorganization may contribute to recovery following mTBI, and that different neural phenotypes may vary in their contribution to this reorganization despite exposure to the same injury.

Developmental remodeling of relay cells in the dorsal lateral geniculate nucleus in the absence of retinal input

BackgroundThe dorsal lateral geniculate nucleus (dLGN) of the mouse has been an important experimental model for understanding thalamic circuit development. The developmental remodeling of retinal projections has been the primary focus, however much less is known about the maturation of their synaptic targets, the relay cells of the dLGN. Here we examined the growth and maturation of relay cells during the first few weeks of life and addressed whether early retinal innervation affects their development. To accomplish this we utilized the math5 null (math5−/−) mouse, a mutant lacking retinal ganglion cells and central projections.ResultsThe absence of retinogeniculate axon innervation led to an overall shrinkage of dLGN and disrupted the pattern of dendritic growth among developing relay cells. 3-D reconstructions of biocytin filled neurons from math5−/− mice showed that in the absence of retinal input relay cells undergo a period of exuberant dendritic growth and branching, followed by branch elimination and an overall attenuation in dendritic field size. However, math5−/− relay cells retained a sufficient degree of complexity and class specificity, as well as their basic membrane properties and spike firing characteristics.ConclusionsRetinal innervation plays an important trophic role in dLGN development. Additional support perhaps arising from non-retinal innervation and signaling is likely to contribute to the stabilization of their dendritic form and function.

Absence of plateau potentials in dLGN cells leads to a breakdown in retinogeniculate refinement.

The link between neural activity and the refinement of projections from retina to the dorsal lateral geniculate nucleus (dLGN) of thalamus is based largely on studies that disrupt presynaptic retinogeniculate activity. Postsynaptic mechanisms responsible for implementing the activity-dependent remodeling in dLGN remain unknown. We tested whether L-type Ca(2+) channel activity in the form of synaptically evoked plateau potentials in dLGN cells is needed for remodeling by using a mutant mouse that lacks the ancillary β3 subunit and, as a consequence, has highly reduced L-type channel expression and attenuated L-type Ca(2+) currents. In the dLGNs of β3-null mice, glutamatergic postsynaptic activity evoked by optic tract stimulation was normal, but plateau potentials were rarely observed. The few plateaus that were evoked required high rates of retinal stimulation, but were still greatly attenuated compared with those recorded in age-matched wild-type mice. While β3-null mice exhibit normal stage II and III retinal waves, their retinogeniculate projections fail to segregate properly and dLGN cells show a high degree of retinal convergence even at late postnatal ages. These structural and functional defects were also accompanied by a reduction in CREB phosphorylation, a signaling event that has been shown to be essential for retinogeniculate axon segregation. Thus, postsynaptic L-type Ca(2+) activity plays an important role in mediating the refinement of the retinogeniculate pathway.

Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Thalamic microcircuits: presynaptic dendrites form two feedforward inhibitory pathways in thalamus

In the visual thalamus, retinal afferents activate both local interneurons and excitatory thalamocortical relay neurons, leading to robust feedforward inhibition that regulates the transmission of sensory information from retina to neocortex. Peculiarly, this feedforward inhibitory pathway is dominated by presynaptic dendrites. Previous work has shown that the output of dendritic terminals of interneurons, also known as F2 terminals, are regulated by both ionotropic and metabotropic glutamate receptors. However, it is unclear whether both classes of glutamate receptors regulate output from the same or distinct dendritic terminals. Here, we used focal glutamate uncaging and whole cell recordings to reveal two types of F2 responses in rat visual thalamus. The first response, which we are calling a Type-A response, was mediated exclusively by ionotropic glutamate receptors (i.e., AMPA and NMDA). In contrast, the second response, which we are calling a Type-B response, was mediated by a combination of ionotropic and type 5 metabotropic glutamate receptors (i.e., mGluR(5)). In addition, we demonstrate that both F2 responses are evoked in the same postsynaptic neurons, which are morphologically distinct from neurons in which no F2 responses are observed. Since photostimulation was relatively focal and small in magnitude, these results suggest distinct F2 terminals, or small clusters of terminals, could be responsible for generating the two inhibitory responses observed. Because of the nature of ionotropic and metabotropic glutamate receptors, we predict the efficacy by which the retina communicates with the thalamus would be strongly regulated by 1) the activity level of a given retinogeniculate axon, and 2) the specific type of F2 terminals activated.

Eye-Specific Projections of Retinogeniculate Axons Are Altered in Albino Mice

The divergence of retinal ganglion cell (RGC) axons into ipsilateral and contralateral projections at the optic chiasm and the subsequent segregation of retinal inputs into eye-specific domains in their target, the dorsal lateral geniculate nucleus (dLGN), are crucial for binocular vision. In albinism, affected individuals exhibit a lack or reduction of pigmentation in the eye and skin, a concomitant reduced ipsilateral projection, and diverse visual defects. Here we investigate how such altered decussation affects eye-specific retinogeniculate targeting in albino mice using the C57BL/6 Tyr(c-2J/c-2J) strain, in which tyrosinase, necessary for melanogenesis, is mutated. In albino mice, fewer RGCs from the ventrotemporal (VT) retina project ipsilaterally, reflected in a decrease in cells expressing ipsilateral markers. In addition, a population of RGCs from the VT retina projects contralaterally and, within the dLGN, their axons cluster into a patch separated from the contralateral termination area. Furthermore, eye-specific segregation is not complete in the albino dLGN and, upon perturbing postnatal retinal activity with epibatidine, the ipsilateral projection fragments and the aberrant contralateral patch disappears. These results suggest that the defects in afferent targeting and activity-dependent refinement in the albino dLGN arise from RGC misspecification together with potential perturbations of early activity patterns in the albino retina.

Epilepsy GeneLGI1Regulates Postnatal Developmental Remodeling of Retinogeniculate Synapses

Retinogeniculate connections undergo postnatal refinement in the developing visual system. Here we report that non-ion channel epilepsy gene LGI1 (leucine-rich glioma-inactivated), mutated in human autosomal dominant lateral temporal lobe epilepsy (ADLTE), regulates postnatal pruning of retinal axons in visual relay thalamus. By introducing an ADLTE-associated truncated mutant LGI1 (836delC) or excess full-length LGI1 into transgenic mice, we found that mutant LGI1 blocks, whereas excess LGI1 accelerates, retinogeniculate axon pruning. The normal postnatal single fiber strengthening was arrested by mutant LGI1 and, contrastingly, was enhanced by excess wild-type LGI1. The maximum response of the retinogeniculate synapses, conversely, remained the same in mature LGI1 transgenic mice, indicating that mutant LGI1 blocks, whereas excess wild-type LGI1 promotes, weak axon fiber elimination. Heterozygous deletion of the LGI1 gene, as found in ADLTE patients, inhibited postnatal retinogeniculate synapse elimination, an effect similar to the ADLTE truncated mutant LGI1. The results identify sensory axon remodeling defects in a sensory aura-associated human epilepsy disorder.

Rapid Plasticity of Visual Responses in the Adult Lateral Geniculate Nucleus

Compared to the developing visual system, where neuronal plasticity has been well characterized at multiple levels, little is known about plasticity in the adult, particularly within subcortical structures. We made intraocular injections of 2-amino-4-phosphonobutyric acid (APB) in adult cats to block visual responses in On-center retinal ganglion cells and examined the consequences on visual responses in the lateral geniculate nucleus (LGN) of the thalamus. In contrast to current views of retinogeniculate organization, which hold that On-center LGN neurons should become silent with APB, we find that ∼50% of On-center neurons rapidly develop Off-center responses. The time course of these emergent responses and the actions of APB in the retina indicate the plasticity occurs within the LGN. These results suggest there is greater divergence of retinogeniculate connections than previously recognized and that functionally silent, nonspecific retinal inputs can serve as a substrate for rapid plasticity in the adult.

Timing of corticogeniculate innervation in the dorsal lateral geniculate nucleus (dLGN) of the mouse relies on retinogeniculate axon innervation

Timing of corticogeniculate innervation in the dorsal lateral geniculate nucleus (dLGN) of the mouse relies on retinogeniculate axon innervation

Rearrangement of Retinogeniculate Projection Patterns after Eye-Specific Segregation in Mice

It has been of interest whether and when the rearrangement of neuronal circuits can be induced after projection patterns are formed during development. Earlier studies using cats reported that the rearrangement of retinogeniculate projections could be induced even after eye-specific segregation has occurred, but detailed and quantitative characterization of this rearrangement has been lacking. Here we delineate the structural changes of retinogeniculate projections in the C57BL/6 mouse in response to monocular enucleation (ME) after eye-specific segregation. When ME was performed after eye-specific segregation, rearrangement of retinogeniculate axons in the dorsal lateral geniculate nucleus (dLGN) was observed within 5 days. Although this rearrangement was observed both along the dorsomedial-ventrolateral and outer-inner axes in the dLGN, it occurred more rapidly along the outer-inner axis. We also examined the critical period for this rearrangement and found that the rearrangement became almost absent by the beginning of the critical period for ocular dominance plasticity in the primary visual cortex. Taken together, our findings serve as a framework for the assessment of phenotypes of genetically altered mouse strains as well as provide insights into the mechanisms underlying the rearrangement of retinogeniculate projections.

The Immune Protein CD3ζ Is Required for Normal Development of Neural Circuits in the Retina

Emerging evidence suggests that immune proteins regulate activity-dependent synapse formation in the central nervous system (CNS). Mice with mutations in class I major histocompatibility complex (MHCI) genes have incomplete eye-specific segregation of retinal ganglion cell (RGC) axon projections to the CNS. This effect has been attributed to causes that are nonretinal in origin. We show that a key component of MHCI receptor, CD3zeta, is expressed in RGCs. CD3zeta-deficient mice have reduced RGC dendritic motility, an increase in RGC dendritic density, and a selective defect of glutamate-receptor-mediated synaptic activity in the retina. Disrupted RGC synaptic activity and dendritic motility is associated with a failure of eye-specific segregation of RGC axon projections to the CNS. These results provide direct evidence of an unrecognized requirement for immune proteins in the developmental regulation of RGC synaptic wiring and indicate a possible retinal origin for the disruption of eye-specific segregation found in immune-deficient mice.

Switching Retinogeniculate Axon Laterality Leads to Normal Targeting but Abnormal Eye-Specific Segregation That Is Activity Dependent

Partial decussation of sensory pathways allows neural inputs from both sides of the body to project to the same target region where these signals will be integrated. Here, to better understand mechanisms of eye-specific targeting, we studied how retinal ganglion cell (RGC) axons terminate in their thalamic target, the dorsal lateral geniculate nucleus (dLGN), when crossing at the optic chiasm midline is altered. In models with gain- and loss-of-function of EphB1, the receptor that directs the ipsilateral projection at the optic chiasm, misrouted RGCs target the appropriate retinotopic zone in the opposite dLGN. However, in EphB1(-/-) mice, the misrouted axons do not intermingle with normally projecting RGC axons and segregate instead into a distinct patch. We also revisited the role of retinal activity on eye-specific targeting by blocking correlated waves of activity with epibatidine into both eyes. We show that, in wild-type mice, retinal waves are necessary during the first postnatal week for both proper distribution and eye-specific segregation of ipsilateral axons in the mature dLGN. Moreover, in EphB1(-/-) mice, refinement of ipsilateral axons is perturbed in control conditions and is further impaired after epibatidine treatment. Finally, retinal waves are required for the formation of the segregated patch of misrouted axons in EphB1(-/-) mice. These findings implicate molecular determinants for targeting of eye-specific zones that are independent of midline guidance cues and that function in concert with correlated retinal activity to sculpt retinogeniculate projections.

Rearrangement of retinogeniculate axons in the dLGN induced by monocular enucleation in mice

Rearrangement of retinogeniculate axons in the dLGN induced by monocular enucleation in mice

Early Retinal Activity and Visual Circuit Development

Does spontaneous retinal activity prior to vision play a role in the establishment of visual maps? In this issue of Neuron, two separate papers by Huberman et al. and Hooks and Chen demonstrate a role for early spontaneous retinal activity in the establishment of ocular dominance columns and synaptic refinement at retinogeniculate synapses.