The Characterization Of Pb2+ Toxicity In Rat Neural Development: An Assessment Of Pb2+ Effects On The Gaba Shift In Neural Networks And Implications For Learning And Memory Disruption
type: CreativeWork
description: The toxic effects of Pb2+ on the developing rat nervous system has been investigated to assess early developmental GABAergic disruption and its implications with altering inhibitory learning and memory. This goal was achieved using a multi-systems approach: blood lead levels (clinical physiology), qRT-PCR (molecular genetics), brain and primary neuronal culture immunology (immunohistochemical and cellular approaches), physiological cellular components (synaptosomes and protein expression) and finally through learning and memory assessment with GABA mimetic drug manipulations in the intact animal (behavioral pharmacology). The influence of a 956ppm Pb2+ gestational diet (i.e. from birth to sacrifice) resulted in pup mean blood lead levels (BLLs measured in Ã¬g/dL) (Range 28-47) and Dams (Range 33-51) respectively. In contrast, control pups and dams were Pb2+ negative. These ages were selected to determine neurodevelopmental trajectories of the GABA-shift from excitation-to-inhibition postnatally in our model. qRT-PCR studies evinced a delay in mRNA expression regulating GAD 80, 65, CACAN Ã¢3, GABAAR and were differentially regulated cortex and hippocampus as a function of age in response to Pb2+. Brain slice immunohistochemistry revealed an early shift of KCC2 expression in both cortex and hippocampus. Notably, these alterations were differentially regulated by age, brain region and subcellular circuitry within structures (i.e. DG vs. CA3). Neuronal cultures revealed that in response to Pb2+ at low micro molar concentrations induced VSCC-Ã¢3 nuclear translocation and GABAAR upregulation. KCC2 expression was inhibiting in cultures by Pb2+. Synaptosomal effects of Pb2+ revealed altered glutamate accumulation and handling with increased spontaneous and decreased evoked release in significantly modulated by Pb exposure suggesting altered brain synaptogenesis. Pb2+ exposure resulted in increased binding suggesting post synaptic modification in cortex and hippocampus incre…
abstract: The toxic effects of Pb2+ on the developing rat nervous system has been investigated to assess early developmental GABAergic disruption and its implications with altering inhibitory learning and memory. This goal was achieved using a multi-systems approach: blood lead levels (clinical physiology), qRT-PCR (molecular genetics), brain and primary neuronal culture immunology (immunohistochemical and cellular approaches), physiological cellular components (synaptosomes and protein expression) and finally through learning and memory assessment with GABA mimetic drug manipulations in the intact animal (behavioral pharmacology). The influence of a 956ppm Pb2+ gestational diet (i.e. from birth to sacrifice) resulted in pup mean blood lead levels (BLLs measured in Ã¬g/dL) (Range 28-47) and Dams (Range 33-51) respectively. In contrast, control pups and dams were Pb2+ negative. These ages were selected to determine neurodevelopmental trajectories of the GABA-shift from excitation-to-inhibition postnatally in our model. qRT-PCR studies evinced a delay in mRNA expression regulating GAD 80, 65, CACAN Ã¢3, GABAAR and were differentially regulated cortex and hippocampus as a function of age in response to Pb2+. Brain slice immunohistochemistry revealed an early shift of KCC2 expression in both cortex and hippocampus. Notably, these alterations were differentially regulated by age, brain region and subcellular circuitry within structures (i.e. DG vs. CA3). Neuronal cultures revealed that in response to Pb2+ at low micro molar concentrations induced VSCC-Ã¢3 nuclear translocation and GABAAR upregulation. KCC2 expression was inhibiting in cultures by Pb2+. Synaptosomal effects of Pb2+ revealed altered glutamate accumulation and handling with increased spontaneous and decreased evoked release in significantly modulated by Pb exposure suggesting altered brain synaptogenesis. Pb2+ exposure resulted in increased binding suggesting post synaptic modification in cortex and hippocampus incre…
author: Neuwirth, Lorenz Simon
keywords: Developmental Biology, Neuroscience and Neurobiology, Toxicology, Brain Excitability, GABAAR, GABA-Shift, Inhibtiory Learning and Memory, Lead Poisoning, VSCC
date published: 2014-02-01T08:00:00Z
date modified: 2026-07-24T01:59:30Z
provider: City University of New York - Graduate Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: The Graduate School and University Center of The City University of New York