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Biomedical subjects

Tomás R Guilarte

Publications and source records attributed to Tomás R Guilarte.

At least 19 recordsLinked to original sources
PubMed2006

Effects of chronic manganese exposure on cognitive and motor functioning in non-human primates.

Acute exposure to manganese is associated with complex behavioral/psychiatric signs that may include Parkinsonian motor features. However, little is known about the behavioral consequences of chronic manganese exposures. In this study, cynomolgus macaque monkeys were exposed to manganese sulfate (10-15 mg/kg/week) over an exposure period lasting 272+/-17 days. Prior to manganese exposure, animals were trained to perform tests of cognitive and motor functioning and overall behavior was assessed by ratings and by videotaped analyses. By the end of the manganese exposure period, animals developed subtle deficits in spatial working memory and had modest decreases in spontaneous activity and manual dexterity. In addition, stereotypic or compulsive-like behaviors such as compulsive grooming increased in frequency by the end of the manganese exposure period. Blood manganese levels measured at the end of the manganese exposure period ranged from 29.4 to 73.7 micro g/l (mean=55.7+/-10.8 (compared to levels of 5.1-14.2 micro g/l at baseline (mean=9.2+/-2.7)), placing them within the upper range of levels reported for human environmental, medical or occupational exposures. These results suggest that chronic exposure to levels of manganese achieved in this study may have detrimental effects on behavior, cognition and motor functioning.

Animals↗
PubMed2006

Evidence for cortical dysfunction and widespread manganese accumulation in the nonhuman primate brain following chronic manganese exposure: a 1H-MRS and MRI study.

Exposure to high levels of manganese (Mn) is known to produce a complex neurological syndrome with psychiatric disturbances, cognitive impairment, and parkinsonian features. However, the neurobiological basis of chronic low-level Mn exposure is not well defined. We now provide evidence that exposure to levels of Mn that results in blood Mn concentrations in the upper range of environmental and occupational exposures and in certain medical conditions produces widespread Mn accumulation in the nonhuman primate brain as visualized by T1-weighted magnetic resonance imaging. Analysis of regional brain Mn distribution using a "pallidal index equivalent" indicates that this approach is not sensitive to changing levels of brain Mn measured in postmortem tissue. Evaluation of longitudinal 1H-magnetic resonance spectroscopy data revealed a significant decrease (p = 0.028) in the N-acetylaspartate (NAA)/creatine (Cr) ratio in the parietal cortex and a near significant decrease (p = 0.055) in frontal white matter (WM) at the end of the Mn exposure period relative to baseline. Choline/Cr or myo-Inositol/Cr ratios did not change at any time during Mn exposure. This indicates that the changes in the NAA/Cr ratio in the parietal cortex are not due to changes in Cr but in NAA levels. In summary, these findings suggest that during chronic Mn exposure a significant amount of the metal accumulates not only in the basal ganglia but also in WM and in cortical structures where it is likely to produce toxic effects. This is supported by a significantly decreased, in the parietal cortex, NAA/Cr ratio suggestive of ongoing neuronal degeneration or dysfunction.

Animals↗
PubMed2006

Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates.

We tested the hypothesis that movement abnormalities induced by chronic manganese (Mn) exposure are mediated by dysfunction of the nigrostriatal dopamine system in the non-human primate striatum. Motor function and general activity of animals was monitored in parallel with chronic exposure to Mn and Positron Emission Tomography (PET) studies of in vivo dopamine release, dopamine transporters and dopamine receptors in the striatum. Analysis of metal concentrations in whole blood and brain was obtained and post-mortem analysis of brain tissue was used to confirm the in vivo PET findings. Chronic Mn exposure resulted in subtle motor function deficits that were associated with a marked decrease of in vivo dopamine release in the absence of a change in markers of dopamine (DA) terminal integrity or dopamine receptors in the striatum. These alterations in nigrostriatal DA system function were observed at blood Mn concentrations within the upper range of environmental, medical and occupational exposures in humans. These findings show that Mn-exposed non-human primates that exhibit subtle motor function deficits have an apparently intact but dysfunctional nigrostriatal DA system and provide a novel mechanism of Mn effects on the dopaminergic system.

Amphetamine↗
PubMed2006

An extended simplified reference tissue model for the quantification of dynamic PET with amphetamine challenge.

BACKGROUND: Equilibrium analysis to quantify dynamic positron emission tomography (PET) with bolus followed by continuous tracer infusion and acute amphetamine challenge assumes that all tissue kinetics attain steady states during pre- and post-challenge phases. Violations of this assumption may result in unreliable estimation of the amphetamine-induced percent change in the binding potential (DeltaBP%). METHOD: We derived an extended simplified reference tissue model (ESRTM) for modeling tracer kinetics in the pre- and post-challenge phases. Ninety-minute [11C]raclopride PET studies with bolus injection followed by continuous tracer infusion were performed on 18 monkeys and 2 baboons. Forty minutes after the bolus injection, a single acute intravenous amphetamine administration was given of 2.0 mg/kg to monkeys and of 0.05, 0.1, 0.5, and 1.5 mg/kg to baboons. Computer simulations further evaluated and characterized the ESRTM. RESULTS: In monkey studies, the DeltaBP% estimated by the ESRTM was 32+/-11, whereas, the DeltaBP% obtained using the equilibrium methods was 32% to 81% lower. In baboon studies, the DeltaBP% values estimated with the ESRTM showed a linear relationship between the DeltaBP% and the natural logarithm of amphetamine dose (R2=0.96), where the DeltaBP%=10.67Ln(dose)+33.79 (0.05<or=dose in mg/kg<or=1.5). At 1.5 mg/kg amphetamine, the DeltaBP% estimates from equilibrium methods were 18% to 40% lower than those estimated by the ESRTM. Results showed that the nonsteady state of tracer kinetics produced an underestimation of the DeltaBP% from the equilibrium analysis. The accuracy of the DeltaBP% estimates from the equilibrium analysis was significantly improved by the ESRTM. The DeltaBP% estimated by the ESRTM in the study was consistent with that from previous [11C] raclopride PET with amphetamine challenge. CONCLUSION: In conclusion, the ESRTM is a robust kinetic modeling approach and is proposed for the quantification of dynamic PET with acute amphetamine stimulation.

Amphetamine↗
PubMed2006

In vivo modulation of the Parkinsonian phenotype by Nrf2.

Oxidative stress has been implicated in the etiology of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. In this report we show that Nrf2, a transcription factor that regulates the expression of phase 2 and antioxidative enzymes, modulates MPTP neurotoxicity in rodents. Nrf2 knockout and wild-type mice were administered MPTP doses ranging from 20 to 60mg/kg. Seven days after MPTP administration dopamine transporter (DAT) levels were measured using [(125)I]-RTI-121 quantitative autoradiography as an index of dopamine terminal integrity in the striatum. The results indicate that MPTP administration resulted in a greater loss of DAT levels in the striatum of Nrf2 knockout mice than in wild-type at all MPTP doses tested. Activation of the Nrf2 pathway by oral administration of the Nrf2 inducer 3H-1,2-dithiole-3-thione (D3T) to wild-type mice produced partial protection against MPTP-induced neurotoxicity. The protective effect of D3T was not due to a change in MPTP metabolism since the level of the MPTP metabolite MPP+ was not significantly different in the D3T treated striatum relative to vehicle control. Administration of D3T to Nrf2 knockout mice did not protect against MPTP neurotoxicity suggesting that the Nrf2 pathway is necessary for the D3T-mediated attenuation of MPTP neurotoxicity. This study demonstrates the significance of activating intrinsic antioxidative mechanisms in an in vivo model of neurodegeneration. The in vivo activation of the Nrf2 pathway in the brain may be an important strategy to mitigate the effects of oxidative stress in neurodegenerative disorders and neurological disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function.

The peripheral-type benzodiazepine receptor or recognition site (PBR) is a widely distributed transmembrane protein that is located mainly in the outer mitochondrial membrane. The PBR binds to high-affinity drug ligands and cholesterol. Many functions are associated directly or indirectly with the PBR, including the regulation of cholesterol transport and the synthesis of steroid hormones, porphyrin transport and heme synthesis, apoptosis, cell proliferation, anion transport, regulation of mitochondrial functions and immunomodulation. Based on these functions, there are many potential clinical applications of PBR modulation, such as in oncologic, endocrine, neuropsychiatric and neurodegenerative diseases. Although "PBR" is a widely used and accepted name in the scientific community, recent data regarding the structure and molecular function of this protein increasingly support renaming it to represent more accurately its subcellular role (or roles) and putative tissue-specific function (or functions). Translocator protein (18kDa) is proposed as a new name, regardless of the subcellular localization of the protein.

Animals↗
PubMed2006

Imaging the peripheral benzodiazepine receptor response in central nervous system demyelination and remyelination.

We used a rodent model of cuprizone-induced demyelination to examine the peripheral benzodiazepine receptor (PBR) response during remyelination. C57BL/6J mice were fed a 0.2% cuprizone-containing or control diet for 3 weeks and then removed to allow for remyelination. Quantitative autoradiography of 3H-(R)-PK11195 binding to PBR in the corpus callosum showed increased levels at 3 weeks of demyelination and gradually decreased as a function of remyelination. PBR levels were associated with the degree of remyelination and activation of microglia and astrocytes. However, the temporal pattern suggests that the PBR signal during the late stages of remyelination was primarily associated with astrocytes. We also used small-animal positron-emission tomography (PET) imaging to determine if this technique could be used to monitor PBR levels in the brain of living mice. The results indicate that 11C-(R)-PK11195 levels are significantly elevated in the mouse brain during cuprizone-induced demyelination and normalize at a time in which remyelination is complete. These findings support the notion that PBR is a sensitive marker for the visualization and quantification of brain injury and recovery. Further, the in vivo imaging of the PBR response is now possible in the living rodent brain.

Animals↗
PubMed2006

Experience-dependent regulation of zif268 gene expression and spatial learning.

Environmental enrichment (EE) is known to enhance the cognitive ability of rodents. To translate EE to the human condition, it is important to understand the parameters of its efficacy. In this study, we examine if the cognitive enhancement associated with EE is permanent and whether a developmental window exists for its efficacy. Rats were housed in continuous isolation (ISO), continuous enrichment (EE), enrichment from postnatal day (PN) 21-50, and then isolation from PN50-79 (PM), or isolation from PN21-50 and then enriched from PN50-79 (CW). Spatial learning ability and basal expression of the immediate-early genes zif268 and Arc as well as the NR1 subunit of the NMDA receptor were assessed. Rats housed in an enriched environment at the time of testing (EE and CW) performed significantly better in the spatial learning task than rats housed in an isolated environment at the time of testing (ISO and PM). Enhanced performance in the spatial learning task was associated with a higher expression of zif268 only in the CA3/CA4 region of the hippocampus. Our study further defines parameters that make environmental enrichment effective in enhancing learning performance and the findings may be helpful in the translation of this intervention to the human condition.

Animals↗
PubMed2005

Acute manganese administration alters dopamine transporter levels in the non-human primate striatum.

We used positron emission tomography (PET) to measure non-invasively the effect of acute systemic administration to manganese sulfate (MnSO4) on dopamine transporter (DAT) levels in the living non-human primate brain. Baboons received [11C]-WIN 35,428 PET scans to measure DAT levels before and after acute MnSO4 administration. In one animal, we observed a 46% increase in DAT binding potential (BP), a measure of DAT binding site availability, 1 week after Mn administration. DAT levels returned to baseline values at 4 months and remained constant at 10 months after treatment. A subsequent single MnSO4 injection to the same animal also resulted in a 57% increase in DAT-BP, 2 days after administration. In a second animal, a 76% increase in DAT-BP relative to baseline was observed at 3 days after Mn injection. In this animal, the DAT-BP returned to baseline levels after 1 month. Using in vitro receptor binding assays, we found that Mn inhibits [3H]-WIN 35,428 binding to rat striatal DAT with an inhibitory constant (Ki) of 2.0+/-0.3mM (n=4). Saturation isotherms and Scatchard analysis of [3H]-WIN 35,428 binding to rat striatal DAT showed a significant decrease (30%, p<0.001) in the maximal number of binding sites (Bmax) in the presence of 2mM MnSO4. No significant effect of Mn was found on binding affinity (Kd). We also found that Mn inhibits [3H]-dopamine uptake with an IC50 of 11.4+/-1.5mM (n=4). Kinetic studies and Lineweaver-Burk analysis showed a significant decrease (40%, p<0.001) in the maximal velocity of uptake (Vmax) with 5mM MnSO4. No significant effect of Mn was found on Michaelis-Menten constant (Km). These in vitro findings suggest that the increase in DAT levels in vivo following acute Mn administration may be a compensatory response to its inhibitory action on DAT. These findings provide helpful insights on potential mechanisms of Mn-induced neurotoxicity and indicate that the DAT in the striatum is a target for Mn in the brain.

Animals↗
PubMed2005

Glutamate carboxypeptidase II levels in rodent brain using [125I]DCIT quantitative autoradiography.

The ability to visualize quantitatively glutamate carboxypeptidase II (GCPII) levels in vivo could advance our understanding of its function in health and disease. In the current study, we synthesized and evaluated a radiolabeled (iodine-125) analog of N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-iodo-L-tyrosine (DCIT), a potent antagonist of GCPII activity. We examined the regional distribution of [125I]DCIT binding in the rodent brain using quantitative autoradiography in order to confirm the validity of this radioligand as a marker of GCPII in the brain. The ultimate goal is to develop an imaging agent for assessing GCPII levels in the living brain. The specific binding of [125I]DCIT to rat brain followed a regional distribution consistent with previous studies describing regional brain GCPII gene expression and activity. We found a modest rostrocaudal gradient in which specific binding of [125I]DCIT to GCPII was lowest in cortical regions, with increasing levels of binding in midbrain structures and high levels of binding in hindbrain and brainstem. Autoradiography of [125I]DCIT in GCPII knockout and wild type mouse brain showed a gene-dose dependency confirming the selectivity of this radioligand for GCPII. We propose that [125I]DCIT is a selective radioligand that can be used to quantify brain GCPII levels in vitro using quantitative autoradiography.

Animals↗
PubMed2005

Calcium/calmodulin-dependent protein kinase II activity and expression are altered in the hippocampus of Pb2+-exposed rats.

In the present study, we examined whether calcium/calmodulin-dependent protein kinase II (CaMKII) is affected by chronic developmental Pb2+ exposure. The effects of Pb2+ exposure on rat hippocampal CaMKII were assessed by measuring CaMKII activity, phosphorylation of CaMKII at threonine-286, and CaMKII alpha and beta protein levels. In the hippocampus of Pb2+-exposed 50-day-old rats known to exhibit deficits in hippocampal long-term potentiation (LTP) and spatial learning, there was a marked reduction (41%) in the apparent maximal velocity (Vmax) of CaMKII and a significant increase (22%) in apparent affinity of the enzyme. These Pb2+-induced changes in CaMKII activity could not be explained by changes in enzyme phosphorylation at threonine-286 or sensitivity to calmodulin. In vitro incubation of hippocampal homogenates from control rats, but not from Pb2+-exposed rats, with Pb2+ prior to assay recapitulated the increase in the affinity of the enzyme observed with in vivo exposure to Pb2+. Western blots of cytosolic and membrane fractions from hippocampus showed a significant decrease in the levels of CaMKII-beta but not alpha protein in the cytosolic fraction of Pb2+-exposed rats. These findings indicate effects of developmental Pb2+ exposure on CaMKII, a component of calcium signaling associated with synaptic plasticity, learning, and memory.

Animals↗
PubMed2005

Lead neurotoxicity: from exposure to molecular effects.

The effects of lead (Pb(2+)) on human health have been recognized since antiquity. However, it was not until the 1970s that seminal epidemiological studies provided evidence on the effects of Pb(2+) intoxication on cognitive function in children. During the last two decades, advances in behavioral, cellular and molecular neuroscience have provided the necessary experimental tools to begin deciphering the many and complex effects of Pb(2+) on neuronal processes and cell types that are essential for synaptic plasticity and learning and memory in the mammalian brain. In this review, we concentrate our efforts on the effects of Pb(2+) on glutamatergic synapses and specifically on the accumulating evidence that the N-methyl-D-aspartate type of excitatory amino acid receptor (NMDAR) is a direct target for Pb(2+) effects in the brain. Our working hypothesis is that disruption of the ontogenetically defined pattern of NMDAR subunit expression and NMDAR-mediated calcium signaling in glutamatergic synapses is a principal mechanism for Pb(2+)-induced deficits in synaptic plasticity and in learning and memory documented in animal models of Pb(2+) neurotoxicity. We provide an introductory overview of the magnitude of the problem of Pb(2+) exposure to bring forth the reality that childhood Pb(2+) intoxication remains a major public health problem not only in the United States but worldwide. Finally, the latest research offers some hope that the devastating effects of childhood Pb(2+) intoxication in a child's ability to learn may be reversible if the appropriate stimulatory environment is provided.

Animals↗
PubMed2004

Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization.

The peripheral benzodiazepine receptor (PBR) has been used as a sensitive marker to visualize and measure glial cell activation associated with various forms of brain injury and inflammation. Previous studies have shown that increased PBR levels following brain injury are specific to areas expressing activated glial cells. However, the contribution of glial cell types responsible for the increases in PBR levels following brain injury is not well defined. In the present study, we used a murine model of cuprizone-induced demyelination to broaden the application of PBR as a marker of brain injury and to validate the relationship between PBR levels and glial cell types. C57BL/6J mice were maintained on a cuprizone-containing or control diet and sacrificed at specific time points after initiation of treatment. Quantitative autoradiography of the PBR-selective ligand [(3)H]-(R)-PK11195 and [(125)I]-(R)-PK11195 showed that increased PBR levels were associated with the degree of demyelination assessed by Black-Gold histochemistry and activation of glial cells assessed by glial fibrillary acidic protein (GFAP) immunohistochemistry for astrocytes and CD11b (Mac-1) for microglia. Our findings indicate that brain PBR levels increased as a function of dose and duration of cuprizone treatment and it was detectable prior to observable demyelination. Increased PBR levels were associated with the degree of demyelination and temporal activation of glial cell types in different anatomical regions. In the corpus striatum, we found a close anatomical correlation between microglial activation and increased PBR levels in demyelinating fibre tracts. In the deep cerebellar nuclei, the temporal increases in PBR paralleled demyelination and microglia and astrocyte activation. On the other hand, in the corpus callosum there was an apparent temporal shift in the increase in PBR levels by different glial cell types from an early and predominantly microglial contribution to a late microglial and astrocytic response. High-resolution emulsion autoradiography of [(3)H]-(R)-PK11195 binding to PBR coupled with GFAP or Mac-1 immunohistochemistry showed that demyelination-induced increases in PBR levels were co-localized to both microglia and astrocytes. These findings support the notion that PBR is a sensitive and specific marker for the in vitro and in vivo visualization and quantification of neuropathological changes in the brain.

Animals↗
PubMed2003

Lead exposure alters cyclic-AMP response element binding protein phosphorylation and binding activity in the developing rat brain.

We examined the effect of lead (Pb(2+)) exposure during development on cyclic-AMP response element binding protein (CREB) expression and phosphorylation in cortical and hippocampal nuclear extracts at postnatal (PN) days 7, 14, 21 and 50. We also examined the binding of CREB family proteins to the cyclic-AMP response element (CRE) using a novel filter-binding assay that provides a quantitative measure of binding kinetics. In the hippocampus and cerebral cortex of control rats, CREB and phospho-CREB (pCREB; serine-133) expression is highest at PN7 and decreases steadily until PN50. Developmental Pb(2+) exposure does not affect total CREB levels but decreases pCREB levels at PN14 and PN50 in the cortex and at PN50 in the hippocampus. Using the filter-binding assay, we measured a 30% decrease in B(max) and 38% decrease in the Kd of CREB family proteins for the CRE in PN50 hippocampal nuclear fractions prepared from Pb(2+)-exposed rats. A similar, but nonsignificant, trend is observed in the cortex of PN50 lead-exposed rats. In addition, a 70% increase in the B(max) was observed in the cortex of PN14 lead-exposed rats without a significant change in the Kd. These disruptions in pCREB expression and binding activity of CREB family members during the ontogeny of the rat brain begin to decipher intracellular mechanisms of Pb(2+) neurotoxicity.

Animals↗
PubMed2003

Selective decrease in NR1 subunit splice variant mRNA in the hippocampus of Pb2+-exposed rats: implications for synaptic targeting and cell surface expression of NMDAR complexes.

We have previously shown that exposure to environmentally relevant levels of Pb(2+) during brain development decreases the expression of N-methyl-D-aspartate receptor (NMDAR) subunit 1 (NR1) and NR2A genes in the hippocampus of young adult rats and was associated with deficits in hippocampal LTP and spatial learning [Neuroscience 99 (2000) 233-242]. In the present study, we demonstrate that the lower levels of NR1 subunit mRNA expressed in the Pb(2+)-exposed hippocampus are principally due to decreased levels of the NR1-4 and NR1-2 splice variants. These changes were present in the absence of changes in GluR1, PSD-95 and alphaCaMKII gene expression. A unique characteristic of these splice variants is that they lack the C1 cassette. Further, these splice variants have been shown to impart the highest cell surface expression, PKC potentiation and calcium kinetics to NMDAR complexes. Our present findings indicate that Pb(2+)-induced changes in NR1 subunit splice variant mRNA expression in the hippocampus may provide a mechanism by which Pb(2+)-exposure can modify NMDAR-mediated calcium signaling and influence the degree of synaptic plasticity.

Alternative Splicing↗
PubMed2003

Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure.

Long-term deficits in cognitive function are the principal effects of lead (Pb2+) exposure in children and can be modeled in experimental animals. Current therapeutic approaches in the treatment of childhood Pb2+ intoxication are not effective in reversing learning deficits once they have occurred. We report that environmental enrichment reverses long-term deficits in spatial learning produced by developmental Pb2+ exposure in rats. Enhanced learning performance of Pb2+-exposed animals reared in an enriched environment was associated with recovery of deficits in N-methyl-D-aspartate receptor subunit 1 (NR1) mRNA and induction of brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. The effect of environmental enrichment on NR1 and BDNF gene expression was specific to Pb2+-exposed animals and was present in the absence of changes in the NR2B subunit of the N-methyl-D-aspartate receptor, GluR1, alpha CamKII, or PSD-95 gene expression measured in the same animals. Our findings demonstrate that the learning impairments and NR1 subunit mRNA deficits resulting from developmental Pb2+ exposure are reversible if the animals are provided with an enriched environment even after the exposure has occurred. We propose environmental enrichment as a basis for the treatment of childhood Pb2+ intoxication.

Age Factors↗
PubMed2002

Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB phosphorylation in the rat brain.

In the present study we show that chronic exposure to low levels of lead (Pb(2+)) during development alters the type of N-methyl-D-aspartate receptor (NMDAR) expressed in the developing and young adult rat brain. Ifenprodil inhibition of [3H]MK-801 binding to the NMDAR channel in cortical and hippocampal neuronal membranes expressed high and low affinity components. Previous studies have shown that the high affinity component is associated with NR1/NR2B receptor complexes while the low affinity component is associated with the appearance and insertion of the NR2A subunit to NMDAR complexes. Pb(2+)-exposed rats express a greater number of [3H]MK-801 binding sites associated with the high affinity and low affinity components of ifenprodil inhibition. Further, [3H]ifenprodil saturation isotherms and Scatchard analysis in cortical and hippocampal membranes showed a higher number of binding sites (B(max)) with no change in binding affinity (K(d)) in Pb(2+)-exposed animals relative to controls. Quantitative [3H]MK-801 autoradiography in response to glutamate and glycine provided evidence that NMDAR complexes in Pb(2+)-exposed rat brain were maximally activated in situ. Higher levels of ifenprodil-sensitive binding sites and increased sensitivity to agonists are properties characteristic of NR1/NR2B recombinant receptors. Thus, our results strongly suggest that a greater proportion of the total number of NMDAR are NR1/NR2B receptors in the Pb(2+)-exposed rat brain. This Pb(2+)-induced change in NMDAR subtypes in the rat brain was associated with reduced CREB phosphorylation in cortical and hippocampal nuclear extracts. These findings demonstrate that chronic exposure to environmentally relevant levels of Pb(2+) altered the subunit composition of NMDAR complexes with subsequent effects on calcium-sensitive signaling pathways involved in CREB phosphorylation.

Animals↗