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Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia.

ABSTRACT: Environmental factors have been associated with psychiatric disorders and recent epidemiological studies suggest an association between prenatal lead (Pb(2+)) exposure and schizophrenia (SZ). Pb(2+) is a potent antagonist of the N-methyl-D-aspartate receptor (NMDAR) and converging evidence indicates that NMDAR hypofunction has a key role in the pathophysiology of SZ. The glutamatergic hypothesis of SZ posits that NMDAR hypofunction results in the loss of parvalbumin (PV)-positive GABAergic interneurons (PVGI) in the brain. Loss of PVGI inhibitory control to pyramidal cells alters the excitatory drive to midbrain dopamine neurons increasing subcortical dopaminergic activity. We hypothesized that if Pb(2+) exposure in early life is an environmental risk factor for SZ, it should recapitulate the loss of PVGI and reproduce subcortical dopaminergic hyperactivity. We report that on postnatal day 50 (PN50), adolescence rats chronically exposed to Pb(2+) from gestation through adolescence exhibit loss of PVGI in SZ-relevant brain regions. PV and glutamic acid decarboxylase 67?kDa (GAD67) protein were significantly decreased in Pb(2+) exposed rats with no apparent change in calretinin or calbindin protein levels suggesting a selective effect on the PV phenotype of GABAergic interneurons. We also show that Pb(2+) animals exhibit a heightened locomotor response to cocaine and express significantly higher levels of dopamine metabolites and D2-dopamine receptors relative to controls indicative of subcortical dopaminergic hyperactivity. Our results show that developmental Pb(2+) exposure reproduces specific neuropathology and functional dopamine system changes present in SZ. We propose that exposure to environmental toxins that produce NMDAR hypofunction during critical periods of brain development may contribute significantly to the etiology of mental disorders.

SUBMITTER: Stansfield KH

PROVIDER: S-EPMC4354343 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia.

Stansfield K H KH Ruby K N KN Soares B D BD McGlothan J L JL Liu X X Guilarte T R TR

Translational psychiatry 20150310

Environmental factors have been associated with psychiatric disorders and recent epidemiological studies suggest an association between prenatal lead (Pb(2+)) exposure and schizophrenia (SZ). Pb(2+) is a potent antagonist of the N-methyl-D-aspartate receptor (NMDAR) and converging evidence indicates that NMDAR hypofunction has a key role in the pathophysiology of SZ. The glutamatergic hypothesis of SZ posits that NMDAR hypofunction results in the loss of parvalbumin (PV)-positive GABAergic inter ...[more]

PMID: 25756805

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Project description:Dysfunction of cortical parvalbumin (PV)-containing GABAergic interneurons has been implicated in cognitive deficits of schizophrenia. In humans microdeletion of the CHRNA7 (?7 nicotinic acetylcholine receptor, nAChR) gene is associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia while in mice similar deletion causes analogous abnormalities including impaired attention, working-memory and learning. However, the pathophysiological roles of ?7 nAChRs in cortical PV GABAergic development remain largely uncharacterized. In both in vivo and in vitro models, we identify here that deletion of the ?7 nAChR gene in mice impairs cortical PV GABAergic development and recapitulates many of the characteristic neurochemical deficits in PV-positive GABAergic interneurons found in schizophrenia. ?7 nAChR null mice had decreased cortical levels of GABAergic markers including PV, glutamic acid decarboxylase 65/67 (GAD65/67) and the ?1 subunit of GABAA receptors, particularly reductions of PV and GAD67 levels in cortical PV-positive interneurons during late postnatal life and adulthood. Cortical GABAergic synaptic deficits were identified in the prefrontal cortex of ?7 nAChR null mice and ?7 nAChR null cortical cultures. Similar disruptions in development of PV-positive GABAergic interneurons and perisomatic synapses were found in cortical cultures lacking ?7 nAChRs. Moreover, NMDA receptor expression was reduced in GABAergic interneurons, implicating NMDA receptor hypofunction in GABAergic deficits in ?7 nAChR null mice. Our findings thus demonstrate impaired cortical PV GABAergic development and multiple characteristic neurochemical deficits reminiscent of schizophrenia in cortical PV-positive interneurons in ?7 nAChR gene deletion models. This implicates crucial roles of ?7 nAChRs in cortical PV GABAergic development and dysfunction in schizophrenia and other neuropsychiatric disorders.

Dataset Information

Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia.

Publications

Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia.

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