Early Activation of Microglia Triggers Long-Lasting Impairment of Adult Neurogenesis in the Olfactory Bulb

Abstract

Microglia, the innate immune cells of the brain, engulf and eliminate cellular debris during brain injury and disease. Recent observations have extended their roles to the healthy brain, but the functional impact of activated microglia on neural plasticity has so far been elusive. To explore this issue, we investigated the role of microglia in the function of the adult olfactory bulb network in which both sensory afferents and local microcircuits are continuously molded by the arrival of adult-born neurons. We show here that the adult olfactory bulb hosts a large population of resident microglial cells. Deafferentation of the olfactory bulb resulted in a transient activation of microglia and a concomitant reduction of adult olfactory bulb neurogenesis. One day after sensory deafferentation, microglial cells proliferate in the olfactory bulb, and their numbers peaked at day 3, and reversed at day 7 after lesion. Similar lesions performed on immunodeficient mice demonstrate that the both innate and adaptive lymphocyte responses are dispensable for the lesion-induced microglial proliferation and activation. In contrast, when mice were treated with an antiinflammatory drug to prevent microglial activation, olfactory deafferentation did not reduce adult neurogenesis, showing that activated microglial cells per se, and not the lack of sensory experience, relates to the survival of adult-born neurons. We conclude that the status of the resident microglia in the olfactory bulb is an important factor directly regulating the survival of immature adult-born neurons.

Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice

“…Indeed, we demonstrated that CsA treatment considerably reduced the number of mice that failed to locate the hidden food and decreased the latency to find the pellet. Our data somewhat contrast a previous work that found that minocycline-induced microglial inhibition had no effect on the recovery of olfactory dysfunction in a Dichlobenil-induced OB damage model [46]. We speculate that these different outcomes of microglial inhibition may be attributed to the differences in olfactory damage between these two models.…”

“…We speculate that these different outcomes of microglial inhibition may be attributed to the differences in olfactory damage between these two models. Dichlobenil induces acute necrosis within the olfactory mucosa accompanied by a severe reduction in the OSN population [46], whereas NPC1 dysfunction tends to cause a gradual OSN loss in a time-dependent manner. Therefore, the benefit of microglial inhibition might be insufficient to overcome the drastic olfactory impairment in the Dichlobenil-treated model.…”

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

“…During the course of aging, however, accumulating injuries to the olfactory system, e.g. by viruses (Majde, 2010) or pollution (Calderon-Garciduenas et al, 2008), may induce excessive neuroinflammation and ultimately lead to well described deterioration of the olfactory system (Lazarini et al, 2012). It is highly conceivable that this in turn will induce pathological changes in relayed brain centers (Koliatsos et al, 2004, Hu et al, 2012.…”

Mast cell–glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide

“…Microglia are probably also key players in developmental synaptic pruning, and disruptions in their number and/or function during the early postnatal period can impair synapse development and plasticity [103]. At the other end of the developmental curve, early activation of microglia can trigger long-lasting impairment of adult neurogenesis in the olfactory bulb [104].…”