Lead (Pb 2+ ) is a ubiquitous environmental neurotoxicant that continues to threaten public health on a global scale. Epidemiological studies have demonstrated detrimental effects of Pb 2+ on childhood IQ at very low levels of exposure. Recently, a mechanistic understanding of how Pb 2+ affects brain development has begun to emerge. The cognitive effects of Pb 2+ exposure are believed to be mediated through its selective inhibition of the N-methyl-D-aspartate receptor (NMDAR). Studies in animal models of developmental Pb 2+ exposure exhibit altered NMDAR subunit ontogeny and disruption of NMDAR-dependent intracellular signaling. Additional studies have reported that Pb 2+ exposure inhibits presynaptic calcium (Ca 2+ ) channels and affects presynaptic neurotransmission, but a mechanistic link between presynaptic and postsynaptic effects has been missing. Recent work has suggested that the presynaptic and postsynaptic effects of Pb 2+ exposure are both due to inhibition of the NMDAR by Pb 2+ , and that the presynaptic effects of Pb 2+ may be mediated by disruption of NMDAR activity-dependent signaling of brainderived neurotrophic factor (BDNF). These findings provide the basis for the first working model to describe the effects of Pb 2+ exposure on synaptic function. Here, we review the neurotoxic effects of Pb 2+ exposure and discuss the known effects of Pb 2+ exposure in light of these recent findings. KeywordsLead; Neurotoxicology; NMDA Receptor; BDNF; Synaptogenesis; Neurotransmission Neurotoxicity of Low-Level Pb 2+ Exposure in ChildrenThe neurological effects of Pb 2+ have been a driving factor in reducing the level of human Pb 2+ exposure from anthropogenic and environmental sources. The first report of the effects of Pb 2+ on the cognitive abilities and social behavior in children was in 1943 [1], however, the full implications of these effects were not appreciated until decades later. Studies from the late 1970s to the early 1990s showed effects of Pb 2+ on cognitive abilities at progressively lower exposures [2]. In 1991, the CDC lowered the definition of Pb 2+ intoxication from 25 µg/dL blood lead level (BLL) to 10 µg/dL BLL, which is the current © Springer Science+Business Media, LLC 2010Correspondence to: Tomás R. Guilarte, trguilarte@columbia.edu. [4][5][6][7]. These studies indicate that the majority of the estimated IQ loss in Pb 2+ -exposed children occurs during the first 10 µg/dL of exposure, and suggest that Pb 2+ may be a non-threshold neurotoxicant [4][5][6][7][8]. NIH Public AccessIn addition to the cognitive deficits associated with Pb 2+ exposure, children with elevated BLLs have behavioral deficits. Several studies have reported that school children with elevated BLLs are more likely to be disruptive in class, display anti-social behavior, and have attention problems [1,[9][10][11][12]. These behavioral effects appear to have an attentiondeficit hyperactivity disorder (ADHD) phenotype; in fact, a recent study identified that childhood Pb 2+ exposure was positively associated with...

Lead (Pb(2+)) exposure is known to affect presynaptic neurotransmitter release in both in vivo and cell culture models. However, the precise mechanism by which Pb(2+) impairs neurotransmitter release remains unknown. In the current study, we show that Pb(2+) exposure during synaptogenesis in cultured hippocampal neurons produces the loss of synaptophysin (Syn) and synaptobrevin (Syb), two proteins involved in vesicular release. Pb(2+) exposure also increased the number of presynaptic contact sites. However, many of these putative presynaptic contact sites lack Soluble NSF attachment protein receptor complex proteins involved in vesicular exocytosis. Analysis of vesicular release using FM 1-43 dye confirmed that Pb(2+) exposure impaired vesicular release and reduced the number of fast-releasing sites. Because Pb(2+) is a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, we tested the hypothesis that NMDAR inhibition may be producing the presynaptic effects. We show that NMDAR inhibition by aminophosphonovaleric acid mimics the presynaptic effects of Pb(2+) exposure. NMDAR activity has been linked to the signaling of the transsynaptic neurotrophin brain-derived neurotrophic factor (BDNF), and we observed that both the cellular expression of proBDNF and release of BDNF were decreased during the same period of Pb(2+) exposure. Furthermore, exogenous addition of BDNF rescued the presynaptic effects of Pb(2+). We suggest that the presynaptic deficits resulting from Pb(2+) exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.

Human exposure to neurotoxic metals is a global public health problem. Metals which cause neurological toxicity, such as lead (Pb) and manganese (Mn), are of particular concern due to the long-lasting and possibly irreversible nature of their effects. Pb exposure in childhood can result in cognitive and behavioural deficits in children. These effects are long-lasting and persist into adulthood even after Pb exposure has been reduced or eliminated. While Mn is an essential element of the human diet and serves many cellular functions in the human body, elevated Mn levels can result in a Parkinson's disease (PD)-like syndrome and developmental Mn exposure can adversely affect childhood neurological development. Due to the ubiquitous presence of both metals, reducing human exposure to toxic levels of Mn and Pb remains a world-wide public health challenge. In this review we summarize the toxicokinetics of Pb and Mn, describe their neurotoxic mechanisms, and discuss common themes in their neurotoxicity.

N-methyl-D-aspartate receptor (NMDAR) ontogeny and subunit expression are altered during developmental lead (Pb 2+ ) exposure. However, it is unknown whether these changes occur at the synaptic or cellular level. Synaptic and extra-synaptic NMDARs have distinct cellular roles, thus, the effects of Pb 2+ on NMDAR synaptic targeting may affect neuronal function. In this communication, we show that Pb 2+ exposure during synaptogenesis in hippocampal neurons altered synaptic NMDAR composition, resulting in a decrease in NR2A-containing NMDARs at established synapses. Conversely, we observed increased targeting of the obligatory NR1 subunit of the NMDAR to the postsynaptic density (PSD) based on the increased colocalization with the postsynaptic protein PSD-95. This finding together with increased binding of the NR2B-subunit specific ligand [ 3 H]-ifenprodil, suggests increased targeting of NR2B-NMDARs to dendritic spines as a result of Pb 2+ exposure. During brain development, there is a shift of NR2B-to NR2A-containing NMDARs. Our findings suggest that Pb 2+ exposure impairs or delays this developmental switch at the level of the synapse. Finally, we show that alter expression of NMDAR complexes in the dendritic spine is most likely due to NMDAR inhibition, as exposure to the NMDAR antagonist aminophosphonovaleric acid (APV) had similar effects as Pb 2+ exposure. These data suggest that NMDAR inhibition by Pb 2+ during synaptogensis alters NMDAR synapse development, which may have lasting consequences on downstream signaling.

Human exposure to heavy metals is a global public health problem. Heavy metals which cause neurological toxicity, such as lead (Pb 2+) and manganese (Mn), are of particular concern due to the long-lasting and possibly irreversible nature of their effects. Pb 2+ exposure in childhood can result in cognitive and behavioral deficits in children. These effects are long-lasting and persist into adulthood even after Pb 2+ exposure has been reduced or eliminated. While Mn is an essential element of the human diet and serves many cellular functions in the human body, elevated Mn levels can result in a Parkinson's disease (PD)-like syndrome and developmental Mn exposure can adversely affect childhood neurological development. Due to the ubiquitous presence of both metals, reducing human exposure to toxic levels of Mn and Pb 2+ remains a worldwide public health challenge. In this review we summarize the toxicokinetics of Pb 2+ and Mn, describe their neurotoxic mechanisms, and discuss common themes in heavy metal toxicology.

Pyrethroid insecticides are one of the most widely used classes of insecticides. Previous studies revealed that pyrethroids potently affect the insect voltage-gated sodium (Na(+)) channel (VGSC), resulting in prolonged channel open time. However, recent findings have suggested that pyrethroids may affect targets other than the VGSC. In particular, several studies have shown that pyrethroids can modulate the activity of voltage-gated calcium (Ca(2+)) channels (VGCCs). However, these studies often reported conflicting results; some studies observed stimulatory effects, whereas others observed inhibitory effects of pyrethroids on VGCCs. This study investigated whether allethrin (AL), a well-characterized type I pyrethroid, altered VGCC characteristics measured by whole-cell recording in rat pheochromocytoma cells (PC12) differentiated with nerve growth factor (NGF). AL (5 microM) increased peak, end, and tail composite VGCC current independent of its effects on VGSCs. After blocking VGCC subtype-specific current with omega-conotoxin GVIA (GVIA, an N-type VGCC antagonist) or nimodipine (NIM, an L-type VGCC antagonist), our data further suggest that AL differentially affects VGCC subtypes. Thus, AL apparently stimulated GVIA-insensitive current while inhibiting NIM-insensitive current. AL also significantly altered the voltage dependency of activation and inactivation of L-type VGCCs. The differential modulation of VGCC subtypes by AL may explain some of the conflicting observations of other studies.

We have previously reported that lead (Pb2+) exposure results in both presynaptic and postsynaptic changes in developing neurons as a result of inhibition of the N-methyl-D-aspartate receptor (NMDAR). NMDAR inhibition by Pb2+ during synaptogenesis disrupts downstream trans-synaptic signaling of brain-derived neurotrophic factor (BDNF) and exogenous addition of BDNF can recover the effects of Pb2+ on both presynaptic protein expression and presynaptic vesicular release. NMDAR activity can modulate other trans-synaptic signaling pathways, such as nitric oxide (NO) signaling. Thus, it is possible that other trans-synaptic pathways in addition to BDNF signaling may be disrupted by Pb2+ exposure. The current study investigated whether exogenous addition of NO could recover the presynaptic vesicular proteins lost as a result of Pb2+ exposure during synaptogenesis, namely Synaptophysin (Syn) and Synaptobrevin (Syb). We observed that exogenous addition of NO during Pb2+ exposure results in complete recovery of whole-cell Syn levels and partial recovery of Syn and Syb synaptic targeting in Pb2+-exposed neurons.

No abstract