PMID- 25756805
OWN - NLM
STAT- MEDLINE
DCOM- 20160120
LR  - 20181113
IS  - 2158-3188 (Electronic)
IS  - 2158-3188 (Linking)
VI  - 5
IP  - 3
DP  - 2015 Mar 10
TI  - Early-life lead exposure recapitulates the selective loss of parvalbumin-positive 
      GABAergic interneurons and subcortical dopamine system hyperactivity present in 
      schizophrenia.
PG  - e522
LID - 10.1038/tp.2014.147 [doi]
AB  - 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.
FAU - Stansfield, K H
AU  - Stansfield KH
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, NY, USA.
FAU - Ruby, K N
AU  - Ruby KN
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, NY, USA.
FAU - Soares, B D
AU  - Soares BD
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, NY, USA.
FAU - McGlothan, J L
AU  - McGlothan JL
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, NY, USA.
FAU - Liu, X
AU  - Liu X
AD  - Department of Biostatistics, Mailman School of Public Health, Columbia 
      University, New York, NY, USA.
FAU - Guilarte, T R
AU  - Guilarte TR
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, NY, USA.
LA  - eng
GR  - R01 ES020465/ES/NIEHS NIH HHS/United States
GR  - P30ES009089/ES/NIEHS NIH HHS/United States
GR  - ES020465/ES/NIEHS NIH HHS/United States
GR  - T32 ES007322/ES/NIEHS NIH HHS/United States
GR  - R01 ES006189/ES/NIEHS NIH HHS/United States
GR  - ES006189/ES/NIEHS NIH HHS/United States
GR  - P30 ES009089/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150310
PL  - United States
TA  - Transl Psychiatry
JT  - Translational psychiatry
JID - 101562664
RN  - 0 (Parvalbumins)
RN  - 2P299V784P (Lead)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Brain/*metabolism
MH  - Chromatography, High Pressure Liquid
MH  - Dopamine/*blood
MH  - Female
MH  - Hyperkinesis/blood/chemically induced
MH  - Interneurons/*metabolism
MH  - Lead/*adverse effects/blood
MH  - Lead Poisoning/blood/complications
MH  - Male
MH  - Parvalbumins/*blood
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects/blood
MH  - Rats
MH  - Rats, Long-Evans
MH  - Risk Factors
MH  - Schizophrenia/*blood/chemically induced
MH  - gamma-Aminobutyric Acid/*blood
PMC - PMC4354343
EDAT- 2015/03/11 06:00
MHDA- 2016/01/21 06:00
PMCR- 2015/03/01
CRDT- 2015/03/11 06:00
PHST- 2014/09/17 00:00 [received]
PHST- 2014/11/25 00:00 [revised]
PHST- 2014/12/19 00:00 [accepted]
PHST- 2015/03/11 06:00 [entrez]
PHST- 2015/03/11 06:00 [pubmed]
PHST- 2016/01/21 06:00 [medline]
PHST- 2015/03/01 00:00 [pmc-release]
AID - tp2014147 [pii]
AID - 10.1038/tp.2014.147 [doi]
PST - epublish
SO  - Transl Psychiatry. 2015 Mar 10;5(3):e522. doi: 10.1038/tp.2014.147.