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Austria - - Ley. Text No. Austria - - Acuerdo internacional. Agreement to supplement the Agreement of 11 November between the Republic of Austria and the Kingdom of Sweden on social security. Done at Vienna.

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Microglia are increasingly shown to be key players in neuron development and synapse connectivity. However, the underlying mechanisms by which microglia regulate neuron function remain poorly understood in part because such analysis is challenging in the brain where neurons and synapses are intermingled and connectivity is only beginning to be mapped. Here, we discuss the features and function of microglia in the ordered mammalian retina where the laminar organization of neurons and synapses facilitates such molecular studies.

We discuss microglia origins and consider the evidence for molecularly distinct microglia subpopulations and their potential for differential roles with a particular focus on the early stages of retina development.

We then review the models and methods used for the study of these cells and discuss emerging data that link retina microglia to the genesis and survival of particular retina cell subtypes. We also highlight potential roles for microglia in shaping the development and organization of the vasculature and discuss cellular and molecular mechanisms involved in this process.

Such insights may help resolve the mechanisms by which retinal microglia impact visual function and help guide studies of related features in brain development and disease. Microglia play potential roles in vascularization, neuron birth and survival, and synapse refinement. Microglia are the resident immune cells of the central nervous system CNS , and emerging work implicates these cells in shaping diverse features of neural development, connectivity, and homeostasis reviewed in [ 1 — 4 ].

However, whether and how particular neuron or synapse types are targeted by microglia and the functional consequences of these interactions are less well described. It has been difficult to answer these questions because circuits in the brain are complex and we know relatively little about them. In this review, we discuss known microglia interactions with neurons in the accessible and well-mapped neural circuits of the mammalian retina.

In the first part of the review, we present an in-depth description of the features of retina microglia and discuss their origins, localization, and organization during development. We also review evidence for microglia subpopulations and present an atlas of microglial biomarkers over development. In the second part, we discuss the functions of microglia, with a focus on their roles in modulating neurogenesis and development, particularly regarding retinal ganglion cells and astrocytes.

In turn, these processes may influence novel roles for microglia in modulating neurovascular organization. Finally, we provide perspectives on key goals for future research, which include potential roles for microglia subpopulations and elucidation of mechanisms by which particular synapses are spared or removed. Continued study of microglia-specific functions in the retina may help inform related studies in the brain and provide unique opportunities to develop microglia targeted treatment strategies in diverse neurological diseases.

Microglia originate from primitive yolk sac progenitors [ 5 , 6 ]. Among these, the transcription factor PU. Microglia genesis is also regulated by the macrophage colony-stimulating factor receptor CSF1R. CSF1R expression on microglia is maintained throughout development. Consistent with the requirement for CSF1R expression, Csf1r knockout mice lack microglia in addition to yolk sac macrophages and osteoclasts [ 8 — 10 ].

Finally, animals lacking toll-like receptor 4 TLR4 display reduced bipolar cell numbers and altered bipolar cell dendritic density, in addition to loss of microglia in the retina. These changes correlate with a significant reduction in retinal function, suggesting a key role for TLR4 in mediating visual function. However, whether microglia are causal to these alterations remains unclear [ 12 ]. After they differentiate, microglia home to the CNS. Microglia can be identified in mouse brain rudiment as early as embryonic day E 8.

They are thought to migrate to the CNS via the embryonic circulatory system as mice that lack the sodium calcium exchanger 1 Ncx-1 have defective blood circulation and microglia fail to enter the brain [ 9 ].

The origins of microglia in the retina and their precise developmental arrival have been less well studied. They are present in human retina by 10 weeks gestation and in mouse retina by E Similar timing has been documented in other species E7 in quail, [ 19 ]; and at E12 in rat, [ 20 ].

Two waves of retinal microglia infiltration have been proposed based on the spatiotemporal localization of these cells. The first wave happens early in development prior to vascularization Fig. At this time, microglia are thought to enter the retina by either: 1 crossing the vitreal retina surface; or 2 migrating from non-neural ciliary regions in the periphery [ 17 , 18 , 21 , 22 ].

A second wave of infiltration has been proposed after blood vessels have formed through invasion from the optic disc or via blood vessels themselves [ 23 ].

Since much of this evidence is correlative, firm documentation of the timing and routes by which microglia enter the retina awaits more contemporary lineage tracing approaches. Schematic of microglia development in mouse retina. Timeline of microglia entry to the retina. Microglia are derived from primitive yolk sac progenitors and are thought to enter the CNS via the circulatory system. Microglia have been documented in the developing murine retina at E Two waves of retinal microglia infiltration have been proposed.

The first wave occurs embryonically and may involve microglia entry through the vitreal retina surface or migration from the ciliary region. A second wave may involve microglia infiltration from the optic disc or via blood vessels.

Schematic of the adult retina. Rod cyan and cone light purple photoreceptors reside in the outer nuclear layer ONL and form connections with interneurons in the outer plexiform layer OPL. Retinal ganglion cells magenta receive this information through synapses in the inner plexiform layer IPL. Their somas reside in the ganglion cell layer GCL along with displaced amacrine cells not pictured.

Microglia cell are found predominately in the inner retina and are largely restricted to the synaptic layers. Microglia entry into the retina coincides with retinal neuron differentiation. Retinal neurons are derived from a precursor pool of retinal progenitor cells RPCs that divide to give rise to the five main types of retinal neurons: photoreceptors, bipolars, amacrines, horizontal cells, and retinal ganglion cells. As these neurons mature they become ordered into three cellular and two synaptic layers.

Photoreceptors comprise the outer nuclear layer ONL and relay information through synapses in the outer plexiform layer OPL to inner retina neurons horizontal, bipolar, and amacrine cells. Bipolar and amacrine cells synapse with retinal ganglion cells in the inner plexiform layer IPL Fig. Microglia comprise 0. Interestingly, microglia are predominately located in the retinal synapse layers Fig. It is perhaps telling that microglia localization tracks the spatial distribution of developing retina synapses.

This localization persists as synapses mature and are refined. This pattern persists into adulthood, with microglia and their processes localizing predominately to the inner retina and OPL, while the ONL is largely devoid of these cells Fig. Thus, microglia are at the right time and place to regulate retina synapse refinement. In line with this idea, the absolute number of retina microglia correlates with the peak of retina synapse pruning. The numbers of retina microglia increase over the first postnatal week, reaching twice that of adult levels by P7 when outer and inner retina synapses area actively refined.

Microglia numbers then steadily decrease until the fourth postnatal week when they reach steady state levels and the retina circuit is considered mature [ 18 ]. At P9, microglia also become present within the developing OPL. This pattern persists into adulthood.

Blue, DAPI; green, microglia. At birth, retinal microglia are amoeboid but become progressively ramified as the retina matures. Morphological changes in microglia are thought to correlate in part with their functional states [ 30 — 32 ]. These terms can be misleading, however, as live imaging suggests that microglia are structurally dynamic in both ramified and amoeboid morphologies, though the cellular functions they carry out may differ.

Ramified microglia actively retract and extend their processes, monitor neurons, and are engaged in metabolite removal and clearance in the CNS reviewed in [ 3 , 34 , 35 ]. In contrast, amoeboid microglia contain numerous lysosomes and phagosomes and are thought to be engaged in synapse, axon, or cell engulfment [ 36 , 37 ].

Consistent with this idea, microglia appear amoeboid in the brain during development at the peak of cell and synapse remodeling and then shift to a ramified state in the first two postnatal weeks [ 38 , 39 ]. This developmental shift in microglia morphology extends to the retina.

At birth, retinal microglia are amoeboid and extend their processes towards the basal side of the retina but become progressively ramified as the retina matures Fig. Shifts in microglia structure also occur in response to CNS injury or pathogen invasion, leading to the formation of reactive amoeboid microglia [ 40 , 41 ]. The mechanisms through which microglia alter their structural states are not well understood.

Koso et al. Continued efforts to understand how microglia achieve different structural states and how these states impact function may aid efforts to modulate microglia activity in development or disease. All microglial precursors express the common macrophage markers CX3 chemokine receptor 1 CX3CR1 and ionized calcium binding adaptor molecule 1 Iba1 [ 14 , 43 ].

Common microglia biomarkers over development are summarized in Fig. Whether microglia can be considered a group of related but distinct cell populations is an area of active investigation. One possibility is that individual microglia can display fluid cellular characteristics that vary according to developmental or disease states.

Alternately, microglia may be comprised of physiologically distinct cell subsets. Progress toward resolving these questions has been somewhat challenging due to the dynamic nature of microglia, their ability to migrate, and the potential for molecular similarities between macrophages that may enter the CNS under some conditions and resident microglia populations [ 48 , 49 ].

However, it is clear that antigenic, structural, and transcriptional differences exist between cohorts of microglia. For example, the cytokine IL appears to demark spatially distinct populations of microglia in the retina. In the presence of neuron degeneration, however, both populations relocate to the retinal pigment epithelium RPE [ 50 ].

For example, CD11c appears more abundant on microglia that are localized to compromised retinal neurons [ 53 ]. Thus, it is tempting to speculate that different subsets of microglia might be tuned to perform niche specific functions or regulate specific neuron types or geographic areas of the CNS. Microglia biomarkers over CNS development. A timeline is presented that summarizes biomarkers for microglia over development in the CNS. For example, Tie2 marks microglia progenitors as early as E7.

Several recent molecular and sequencing based profiling studies also support the presence of microglia subpopulations in brain and retina. These populations appear dynamic and vary with developmental time and the presence or absence of disease [ 54 — 56 ]. But some common features emerge: 1 microglia are among the most transcriptionally diverse cell types in the brain; 2 their activation states can be spatially distinct within both normal and abnormal CNS environments; and 3 developing microglia can share transcriptional similarities with those in aged or diseased environments [ 54 — 56 ].

In a particularly thorough study, Hammond et al. This approach identified 9 transcriptional subpopulations of microglia that remained consistent across all ages and disease states.

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