title: Presynaptic mechanisms of lead neurotoxicity: effects on vesicular release, vesicle clustering and mitochondria number.
abstract: Childhood lead (Pb2+) intoxication is a global public health problem and accounts for 0.6% of the global burden of disease associated with intellectual disabilities. Despite the recognition that childhood Pb2+ intoxication contributes significantly to intellectual disabilities, there is a fundamental lack of knowledge on presynaptic mechanisms by which Pb2+ disrupts synaptic function. In this study, using a well-characterized rodent model of developmental Pb2+ neurotoxicity, we show that Pb2+ exposure markedly inhibits presynaptic vesicular release in hippocampal Schaffer collateral-CA1 synapses in young adult rats. This effect was associated with ultrastructural changes which revealed a reduction in vesicle number in the readily releasable/docked vesicle pool, disperse vesicle clusters in the resting pool, and a reduced number of presynaptic terminals with multiple mitochondria with no change in presynaptic calcium influx. These studies provide fundamental knowledge on mechanisms by which Pb2+ produces profound inhibition of presynaptic vesicular release that contribute to deficits in synaptic plasticity and intellectual development.
authors.affiliation: Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Guariglia
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McGlothan
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.
authors.forename: Kirstie H
authors.initials: KH
authors.lastname: Stansfield
authors.affiliation: Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Patric K
authors.initials: PK
authors.lastname: Stanton
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.
authors.forename: Tomás R
authors.initials: TR
authors.lastname: Guilarte
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000503:physiopathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D007854:Lead / Q000633:toxicity*; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D013572:Synaptic Vesicles / Q000187:drug effects*
chemical_list: D007854:Lead