Inflammation Regulates Functional Integration of Neurons Born in Adult Brain

Abstract

Inflammation influences several steps of adult neurogenesis, but whether it regulates the functional integration of the new neurons is unknown. Here, we explored, using confocal microscopy and whole-cell patch-clamp recordings, whether a chronic inflammatory environment affects the morphological and electrophysiological properties of new dentate gyrus granule cells, labeled with a retroviral vector encoding green fluorescent protein. Rats were exposed to intrahippocampal injection of lipopolysaccharide, which gave rise to longlasting microglia activation. Inflammation caused no changes in intrinsic membrane properties, location, dendritic arborization, or spine density and morphology of the new cells. Excitatory synaptic drive increased to the same extent in new and mature cells in the inflammatory environment, suggesting increased network activity in hippocampal neural circuitries of lipopolysaccharide-treated animals. In contrast, inhibitory synaptic drive was more enhanced by inflammation in the new cells. Also, larger clusters of the postsynaptic GABA A receptor scaffolding protein gephyrin were found on dendrites of new cells born in the inflammatory environment. We demonstrate for the first time that inflammation influences the functional integration of adult-born hippocampal neurons. Our data indicate a high degree of synaptic plasticity of the new neurons in the inflammatory environment, which enables them to respond to the increase in excitatory input with a compensatory upregulation of activity and efficacy at their afferent inhibitory synapses.

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

“…68 Adult new-born neurons are susceptible to brain inflammation. 38,39 Anti-inflammatory treatments prevent chronic brain inflammationmediated decreased neurogenesis. [68][69][70] Alterations of the number and/or morphology of microglial cells, as well as the up-regulation of inflammatory cytokines, such as IL-1a, IL-6, TNFa, have been implicated in cognitive and behavioral changes observed in depressed subjects.…”

“…Adult-born hippocampal neurons are sensitive to microglial activation, which can compromise survival and differentiation of newly-formed neurons. 38,39 Increased inflammation in the brain after SCI has been reported not only in pain regulatory areas, such as the brainstem and thalamus, but also in the hippocampus and cerebral cortex. 18,19,21,36,40,41 Moreover, SCI significantly increases M1-like microglial activation genes in the hippocampus, along with changes in M2a-like and M2c-like markers.…”

Impact of diet on adult hippocampal neurogenesis

“…AHN is also influenced by many other pathological conditions. For example, it is increased in epilepsy [44] and stroke [115], whereas it is decreased in HIV infection [87], and the integration of newborn neurons is disrupted by CNS inflammation [41]. It is apparent that AHN is influenced by neurological diseases; however, further studies are needed to understand the roles and consequences of AHN changes in pathological events.…”

Protection of Hippocampal Neurogenesis from Toll-Like Receptor 4-Dependent Innate Immune Activation by Ablation of Prostaglandin E2 Receptor Subtype EP1 or EP2

“…30 -35 Interestingly, SGZ IPCs that survive the inflammatory stress induced by LPS can differentiate and integrate as granule neurons, although with a heightened degree of synaptic plasticity. 36 Importantly, LPS-induced microglial activation and subsequent depletion of SGZ IPCs can be blocked by indomethacin, 33 an inhibitor of COX-1 and COX-2, as well as NS398, 35 a relatively COX-2-selective inhibitor, strongly suggesting involvement of the PG pathway, although other pharmacological activities have been ascribed to these drugs in addition to COX isozyme inhibition. 37 The studies presented here tested the hypothesis that paracrine depletion of SGZ IPCs by innate immune activation is critically regulated by EP1 or EP2 expression.…”