Involvement of Microglia Activation in the Lead Induced Long-Term Potentiation Impairment

Abstract

Exposure of Lead (Pb), a known neurotoxicant, can impair spatial learning and memory probably via impairing the hippocampal long-term potentiation (LTP) as well as hippocampal neuronal injury. Activation of hippocampal microglia also impairs spatial learning and memory. Thus, we raised the hypothesis that activation of microglia is involved in the Pb exposure induced hippocampal LTP impairment and neuronal injury. To test this hypothesis and clarify its underlying mechanisms, we investigated the Pb-exposure on the microglia activation, cytokine release, hippocampal LTP level as well as neuronal injury in in vivo or in vitro model. The changes of these parameters were also observed after pretreatment with minocycline, a microglia activation inhibitor. Long-term low dose Pb exposure (100 ppm for 8 weeks) caused significant reduction of LTP in acute slice preparations, meanwhile, such treatment also significantly increased hippocampal microglia activation as well as neuronal injury. In vitro Pb-exposure also induced significantly increase of microglia activation, up-regulate the release of cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS) in microglia culture alone as well as neuronal injury in the co-culture with hippocampal neurons. Inhibiting the microglia activation with minocycline significantly reversed the above-mentioned Pb-exposure induced changes. Our results showed that Pb can cause microglia activation, which can up-regulate the level of IL-1β, TNF-α and iNOS, these proinflammatory factors may cause hippocampal neuronal injury as well as LTP deficits.

Lead Exposure Impairs Hippocampus Related Learning and Memory by Altering Synaptic Plasticity and Morphology During Juvenile Period

“…Multitargets could be involved. In our previous study, we found that Pb exposure caused LTP impairment through the release of cytokine by the activated microglia [21]. In this study, we found that AMPA receptor phosphorylation and NR2A downregulation could possibly contribute to LTP impairment and development of dendritic spine change, which could be the cause of the behavior change of Pb-treated rats.…”

Lead induces COX-2 expression in glial cells in a NFAT-dependent, AP-1/NFκB-independent manner

“…For instance, incubation of lead at the concentrations of 0.25–1.0 μM (5.2–20.7 μg/dL) for 7–21 days resulted in an obvious reduction in functions of primary cultures of rat astrocytes (Lidsky and Schneider, 2003). Our published studies showed that short-term treatment of lead (within 48 h) at 50 μM (1035.2 μg/dL) activated the primary cultured rat microglia (Liu et al, 2012). To further reveal the molecular basis for lead activation of microglia, we used acute lead exposure here since COX-2 is an immediate early response gene, and during our observance periods (within 24 h), no severe cell death was observed.…”

Original Research: The expression of MMP2 and MMP9 in the hippocampus and cerebral cortex of newborn mice under maternal lead exposure

“…1 One of the heavy metals, lead has threatened environment sustainability and our future generations. Although research on lead neurotoxicity has been of interest for many years, [2][3][4][5][6][7] the effects of lead on the expression of MMP2 and MMP9 in the cerebral cortex and hippocampus still need to be elucidated.…”