Molecular neurobiology of lead (Pb(2+)): effects on synaptic function

Abstract

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 brain-derived 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.

Scheme 1

Working model of molecular mechanism(s) by which chronic Pb²⁺ exposure disrupts synapse formation and plasticity in developing hippocampal neurons. Green arrows indicate normal processes; red arrows indicate Pb²⁺-impaired processes. In normal glutamatergic synapses, glutamatergic vesicles undergo Ca²⁺-dependent fusion with the plasma membrane in response to presynaptic signals (a). This process is mediated by the interaction with the v-SNARE Synaptobrevin and the t-SNAREs Syntaxin or SNAP-25. As a result of vesicular fusion, glutamate (Glu) is released from presynaptic terminals, resulting in NMDAR activation (b). Ca²⁺ enters the postsynaptic cell through synaptic NMDARs, activating downstream intracellular pathways. Under normal conditions, the predominant NMDARs at mature synapses are NR2A-NMDARs, which are linked to CREB phosphorylation (c). Activity-dependent CREB activation results in transcription of BDNF, which is transported and released in an activity-dependent retrograde fashion. Secreted BDNF interacts with the tropomyosin-related kinase receptor B (TrkB) (d). In the presynaptic neuron, BDNF activation of TrkB increases the number of docked vesicles and enhances vesicular release, as well as increases the incorporation of Syn and Syb into synaptic vesicles (e). During chronic Pb²⁺ exposure, however, Ca²⁺ influx through synaptic NMDAR is inhibited [1]. This causes a reduction in NR2A-NMDARs while NR2B-NMDARs are increased, possibly at extrasynaptic sites. As a result of reduced NR2A-NMDAR activation, NR2B-NMDARs are operational and are coupled to a CREB shut-off pathway. Reduced CREB signaling during Pb²⁺ exposure may result in decreased BDNF protein levels [2]. BDNF secretion is impaired during Pb²⁺ exposure [3], resulting in reduced activation of presynaptic TrkB receptors by BDNF [4]. Without positive feedback, there is reduced incorporation of synaptic vesicle proteins Syn and Syb and impaired vesicular release that can be rescued by exogenous addition of BDNF