Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina

Abstract

Microglia, the principal resident immune cell of the CNS, exert significant influence on neurons during development and in pathological situations. However, if and how microglia contribute to normal neuronal function in the mature uninjured CNS is not well understood. We used the model of the adult mouse retina, a part of the CNS amenable to structural and functional analysis, to investigate the constitutive role of microglia by depleting microglia from the retina in a sustained manner using genetic methods. We discovered that microglia are not acutely required for the maintenance of adult retinal architecture, the survival of retinal neurons, or the laminar organization of their dendritic and axonal compartments. However, sustained microglial depletion results in the degeneration of photoreceptor synapses in the outer plexiform layer, leading to a progressive functional deterioration in retinal light responses. Our results demonstrate that microglia are constitutively required for the maintenance of synaptic structure in the adult retina and for synaptic transmission underlying normal visual function. Our findings on constitutive microglial function are relevant in understanding microglial contributions to pathology and in the consideration of therapeutic interventions that reduce or perturb constitutive microglial function.

Microglia Are Irrelevant for Neuronal Degeneration and Axon Regeneration after Acute Injury

“…These cells represent either PLX-resistant, nondepleted microglia or infiltrated macrophages. PLX5622-induced retinal microglia deficiency was also more pronounced compared with a genetic approach, which showed only nearcomplete depletion and some long-term repopulation (Wang et al, 2016). Treatment times might possibly be reducible, but we found that 1 week of PLX5622 diet was insufficient to achieve complete depletion, similar to previous studies in brain .…”

“…As described previously, Iba1-positive cells were detected in the GCL, IPL, and OPL (Fig. 1A-C) (Wang et al, 2016) and the entire optic nerves (Fig. 1D) of untreated mice.…”

“…Treatment times might possibly be reducible, but we found that 1 week of PLX5622 diet was insufficient to achieve complete depletion, similar to previous studies in brain . Moreover, other cells of the nervous system, such as RGCs, astrocytes, oligodendrocyte lineage cells, and peripheral macrophages in the spleen, also remained unaffected upon PLX5622 treatment (Szalay et al, 2016;Wang et al, 2016).…”

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

“…Microglial cells are implicated in the maintenance of synaptic integrity [62] and, in fact, could promote learning-dependent synaptic formation [41]. In addition, microglia is involved in Abeta phagocytosis [27, 64, 65], senile plaque compaction, and limitation of Abeta toxicity [7, 66].…”

Central Nervous System: (Immunological) Ivory Tower or Not?

“…The short-term effects of such drastic approaches appear to be subtle, expressed as mild cognitive impairments (Parkhurst et al, 2013) or with no behavioral effects at all (Elmore et al, 2014). Ablation of microglia does not induce neuronal loss, but longer-term ablation can cause synaptic degradation (Parkhurst et al, 2013;Spangenberg et al, 2016;Wang et al, 2016). Intriguingly, in mouse models of Alzheimer's disease with its hallmark microglial activation and proliferation, the effects of microglial ablation are beneficial (Hong et al, 2016;Olmos-Alonso et al, 2016;Spangenberg et al, 2016).…”