Modulation of adult-born neurons in the inflamed hippocampus

Abstract

Throughout life new neurons are continuously added to the hippocampal circuitry involved with spatial learning and memory. These new cells originate from neural precursors in the subgranular zone of the dentate gyrus, migrate into the granule cell layer, and integrate into neural networks encoding spatial and contextual information. This process can be influenced by several environmental and endogenous factors and is modified in different animal models of neurological disorders. Neuroinflammation, as defined by the presence of activated microglia, is a common key factor to the progression of neurological disorders. Analysis of the literature shows that microglial activation impacts not only the production, but also the migration and the recruitment of new neurons. The impact of microglia on adult-born neurons appears much more multifaceted than ever envisioned before, combining both supportive and detrimental effects that are dependent upon the activation phenotype and the factors being released. The development of strategies aimed to change microglia toward states that promote functional neurogenesis could therefore offer novel therapeutic opportunities against neurological disorders associated with cognitive deficits and neuroinflammation. The present review summarizes the current knowledge on how production, distribution, and recruitment of new neurons into behaviorally relevant neural networks are modified in the inflamed hippocampus.

Keywords: adult neurogenesis; chemokines; cytokines; inflammation; microglia.

FIGURE 1

Schematic drawing representing the impact of classical (depicted in red) and alternative (depicted in blue) activation of microglia on adult-born neurons (depicted in green) in the hippocampus. In response to changes in the microenvironment microglia can undergo to a potentially neurotoxic “classical activation” (characterized by the release of proinflammatory factors) or a potentially neuroprotective “alternative activation” (characterized by the release of anti-inflamatory cytokines). Polarization toward classical activation can be induced experimentally by exposure to pro-inflammatory cytokines such as (IFN)-gamma, tumor necrosis factor (TNF)-alpha and interleukin (Il)-1beta, as well as bacterial-derived LPS. Classically activated microglia has been shown to: (1) decrease the production of neurons, (2) alter their migration pattern, and (3) reduce their recruitment into neuronal networks (red arrows). Alternative activation of microglia can be induced experimentally by anti-inflammatory cytokines such as Il-4 and Il-13 and can increase the production of neurons (blue arrow). The impact of alternative activation of microglia on the migration and the integration of new neurons remains unknown.