NMDA Receptor Function in Lead Neurotoxicity

? DESCRIPTION (provided by applicant): Epidemiological studies during the last decade have described an association between chronic early life lead (Pb2+) exposure (CELLE) and mental disorders later in life, for example schizophrenia (SZ). There is scientific evidence that some of these mental health problems are the result of alterations in the function of the N- methyl-D-aspartate receptors (NMDAR) complex. The NMDAR is important for brain development, synaptic plasticity, learning and memory; and, Pb2+ is a potent inhibitor of the NMDAR. During the last 20 years, the long-term goals of the research funded by this grant has been to elucidate the molecular and cellular mechanisms by which CELLE affects brain development and impairs synaptic plasticity and cognitive function via NMDAR inhibition. Our current studies are defining molecular and cellular changes resulting from CELLE that resembles those associated with SZ. For example, CELLE results in the loss of parvalbumin-positive GABAergic interneurons (PVGI) in the frontal cortex and hippocampus of adolescent rats, neuropathology that is hallmark of SZ and is duplicated by NMDAR antagonist animal models of SZ. We also found that CELLE results in a hyperactive subcortical dopaminergic system and increases D2-dopamine receptor levels in the striatum, two features present in SZ subjects. The goal of the proposed studies is to determine the developmental trajectory of the PVGI loss produce by CELLE and the downstream effects on gamma oscillations (gamma-osc) and ultimately on cognitive function. We are focusing on PVGI because they are fast- spiking GABAergic inhibitory neurons that synchronize pyramidal cell firing, giving rise to gamma-osc that are critical for cognitive functio and PVGI development depends on NMDAR function. The proposed gamma-osc studies will provide a neural network link to the PVGI loss and behavioral and cognitive function deficits in adolescent and young adult Pb2+-exposed rats. We also propose to test D-serine as a pharmacological therapy that may mitigate the behavioral and cognitive function deficits resulting from early life Pb2+ intoxication. At the present time there is no pharmacological intervention that mitigates the behavioral and learning deficits resulting from Pb2+ intoxication i children.