* National Research Council, Washington, DC 20001; Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and
Department of Psychology, University of North Carolina, North Carolina 27599
1 To whom correspondence should be addressed at Neurotoxicology Division (MD-B10505), National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-4849. E-mail: gilbert.mary{at}epa.gov.
Received December 8, 2004; accepted January 12, 2005
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ABSTRACT |
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Key Words: hypothyroidism; hippocampus; paired-pulse facilitation; long-term potentiation; extracellular signal-regulated kinase; adult.
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INTRODUCTION |
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Until recently, few experimental studies have been conducted to model the effects of subtle thyroid hormone insufficiency on early brain development or to evaluate the dose-response relationships between altered serum hormones and brain insult. Berbel and colleagues (Auso et al., 2004; Lavado-Autric et al., 2003
) have reported cortical and hippocampal neuronal misplacements in the offspring of dams experiencing brief and mild reductions in thyroid hormones during gestation and lactation. A number of genes critical for cell proliferation, migration, and myelination have been identified, which are regulated by thyroid hormone (Bernal, 2002
; Bernal et al., 2003
; Oppenheimer and Schwartz, 1997
; Thompson and Potter, 2000
). Most of these studies, designed to evaluate the role of thyroid hormones on gene expression, have utilized a model of severe hypothyroidism. What has been lacking is a link between perturbations in gene expression, structural abnormalities, and brain function and an evaluation of the dose-response relationships following mild disruptions of the thyroid axis (Bernal et al., 2003
; Forrest, 2004
; Thompson and Potter, 2000
; Zoeller, 2003
). The current study was performed to provide information on the functional consequences of early hormone insufficiency in a brain slice preparation well suited for investigation of physiological, morphological, and molecular substrates. Synaptic transmission and plasticity were examined in the hippocampus, a structure known to be sensitive to thyroid hormone disruption and to play a critical role in some types of learning and memory. Offspring of thyroid-deficient dams in which a graded level of hormone insufficiency was produced were evaluated to begin to define the long-term consequences of milder forms of thyroid hormone insufficiency.
The primary health outcome of concern resulting from early thyroid hormone insufficiency is intellectual impairment. The deleterious effects of severe developmental hypothyroidism on the hippocampal morphology have been well established (Madeira et al., 1992; Rami et al., 1986
). Perturbations in thyroid hormone function are associated with behavioral impairments in tasks requiring integrity of the hippocampus (Akaike et al., 1991
; Darbra et al., 2004
; Guadano-Ferraz et al., 2003
). Recently, electrophysiological studies have also demonstrated that hypothyroidism induced by propylthiouracil (PTU) or methimazole exposure alters synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus (Niemi et al., 1996
; Sui and Gilbert, 2003
; Vara et al., 2002
). The best model system to investigate the synaptic basis of cognition is long-term potentiation (LTP) in the hippocampus (Malenka and Nicoll, 1999
), and long-term changes in hippocampal synaptic strength are generally accepted to be involved in learning and memory (Bliss and Collingridge, 1993
; Brown et al., 1990
). More recently, short-term synaptic plasticity as measured by paired-pulse functions has also been proposed to play a functional role in temporal information processing and reflect mechanisms important for learning (Buonomano and Merzenich, 1995
; Dobrunz et al., 1997
; Lisman, 1997
; Silva et al., 1996
). LTP and paired-pulse facilitation are reduced in area CA1 of slices from neonatal rats that remained hormone deficient at the time of assessment (Sui and Gilbert, 2003
; Vara et al., 2002
). In the present study, the persistence of these impairments was investigated in adults following recovery from hormone insufficiencies endured during development.
Regulation of the expression and phosphorylation of a number of synaptic proteins are under the control of thyroid hormones (Bernal, 2002; Bernal et al., 2003
; Davis et al., 2002
; Lin et al., 1999
; Thompson and Potter, 2000
). Many of these same proteins are also necessary for normal synaptic transmission, short-term and long-term plasticity, and hippocampal-based learning (Atkins et al., 1998
; Benowitz and Routtenberg, 1997
; Blum et al., 1999
; English and Sweatt, 1996
, 1997
; Gerendasy et al., 1994
; Impey et al., 1999
; Klann et al., 1992
; Oestreicher et al., 1997
; Rosahl et al., 1993
; 1995
; Selcher et al., 1999
; Winder et al., 1999
). Thus, in addition to physiological assessments, levels of synapsin, growth associated protein 43 (GAP-43), neurogranin (RC3), and mitogen-activated protein kinase (MAPK) were examined in area CA1 of the hippocampus. A second aim of the present study was to determine if perturbations in the expression or activation of these proteins persist upon recovery of normal thyroid hormone status and could underlie alterations in synaptic function and behavior that are maintained in adult animals.
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MATERIALS AND METHODS |
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Slice preparation and electrophysiological recording.
At the age of 1114 week (PN77PN96), one male offspring was randomly selected from each litter (0 ppm, n = 12 litters; 3 ppm, n = 15 litters; 10 ppm, n = 8 litters), sacrificed by decapitation, and prepared for slice electrophysiology as described previously (Sui and Gilbert, 2003). Trunk blood was collected at the time of sacrifice and stored for hormone analysis. The brain was removed, and the hippocampus was dissected on ice. Transverse hippocampus slices (400 µm) were cut using a McIlwain tissue chopper and placed in ice-cold, oxygenated artificial cerebrospinal fluid (ACSF, 124 mM NaCl, 3 mM KCl, 2.0 mM MgSO4, 2 mM CaCl2, 1.25 mM NaH2PO4, 26 mM NaHCO3, 10 mM glucose, pH 7.4). Slices were immediately transferred to an interface recording chamber containing warmed, oxygenated (95% O2/5% CO2) ACSF and incubated at 33°C for a minimum of 1 h prior to recording. Biphasic squarewave pulses were delivered through a stainless steel electrode placed in the stratum radiatum, and stimulation-evoked extracellular field potentials were recorded from both the pyramidal cell layer and the stratum radiatum of CA1 through glass micropipettes (24 µm tip diameter) filled with ACSF. Stability of baseline recordings was established by delivering single pulses (1/min, 0.1 ms pulse width at an intensity yielding 7080% of maximal population spike amplitude for a given slice) for 1520 min prior to recording. When the variation in field potential amplitude was less then ±10%, the baseline was considered stable. Slices with unstable baseline responses were excluded from further experimentation.
Input-output (I/O) functions were collected to examine baseline synaptic transmission by delivering an ascending series of 14 stimulus intensities (20150 µA) that ranged from subthreshold for elicitation of an excitatory postsynaptic potential (EPSP) to those eliciting maximal responses. Five pulses were delivered at each stimulus intensity at a frequency of 0.1 Hz and averaged at each recording site. Following collection of the I/O function, paired-pulse facilitation of the dendritic EPSP was measured at ten interpulse intervals (201000 ms) at maximal (150 µA) and submaximal (100110 µA) stimulus strengths. Finally, LTP of somatic population spike and dendritic EPSP was induced. A test stimulus was chosen of intensity sufficient to produce a population spike approximately 7080% of maximum. Pretrain responses were recorded for 20 min, followed by theta burst stimulation (25 4-pulse bursts at 100 Hz, 200 ms between bursts at the same stimulus intensity as the pretrain pulse). Single pulse recording resumed immediately following the train delivery and continued for 60 min.
Waveform scoring.
Action potentials in pyramidal cell neurons are reflected in field potentials recordings from the pyramidal cell layer as a large negative going potential, the population spike (Bliss and Richards, 1971). The dendritic responses recorded from the stratum radiatum provide an index of synaptic activity comprising the summed population excitatory postsynaptic potentials (EPSP) (Bliss and Richards, 1971
). Population spike amplitude was estimated by calculating the voltage difference between the most negative point of the spike and a tangent connecting the onset of the spike and the next positive peak on the waveform. At the dendritic site, EPSP slope was calculated as the rate of amplitude change for the initial negative deflection to the peak. The EPSP peak amplitude was the most negative point on the waveform, and the EPSP area measure was initiated at the point of the initial negative deflection and ended with the return of the EPSP to the baseline. For I/O functions, response amplitude was normalized to the percentage of maximal population spike amplitude and EPSP slope. Paired-pulse facilitation and depression were expressed as the ratio of the mean amplitude of the second response relative to the first (pulse 2/pulse 1 x 100). LTP was expressed as percent change from the mean of ten pretrain recordings taken just prior to train delivery.
Sample preparation for ERK1 and ERK2 analysis.
LTP-induced phosphorylation of the extracellular signal regulated kinases (ERK1 and ERK2) of the MAPK family of kinases was investigated in a different set of hippocampal slices harvested from the same animals used for electrophysiological assessments. To prepare these samples, slices were maintained in the same interface chamber as those used for electrophysiological recordings and were allowed to incubate at 33°C for at least 1 h. Pairs of slices either were left unstimulated or received the same train stimulation as that used to induce LTP. Slices were removed from the recording chamber 3 min after train delivery and frozen on dry ice. The CA1 subregion surrounding the recording site was harvested by a single punch with a glass pipette, 1 mm in diameter. Punches from 78 slices from the same animal were pooled together and stored at 80°C for later analyses by Western blot.
Sample preparation for synapsin, GAP-43, and RC3 analysis.
Levels of synaptic proteins synapsin, GAP-43, and neurogranin (RC3) were examined in area CA1 of hippocampus of adult male littermates of animals used for electrophysiology. Animals were sacrificed by decapitation, the hippocampus was removed, and the midtemporal region dissected. Tissue consisting primarily of area CA1 was extracted by cutting along the hippocampal fissure and was stored at 80°C for later analyses.
Western blot analysis.
For Western blot analyses, tissue was homogenized by sonication in ice-cold solubilizing buffer containing 1% Triton X-100, 20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 10% glycerol, 1 mM NaF, 1 mM Na3VO4, and 0.5% protease inhibitors (Protease Inhibitor Cocktail III, Calbiochem, La Jolla, CA). The insoluble material was removed by centrifugation at 10,000 x g for 10 min at 4°C. An aliquot of the supernatant was taken for protein determination, and the remaining supernatant was added to an equal volume of Laemmli's sample buffer (BioRad, Hercules, CA), and samples were boiled at 100°C for 5 min. Samples were resolved by SDSPAGE followed by electrophoretic transfer onto a nitrocellulose membrane (Bio-Rad, Hercules, CA). The blots were blocked for 1 h with 5% nonfat dried milk at room temperature, then incubated overnight at 4°C with commercially available specific antibodies to the proteins of interest. After three short washes, the blots were incubated for 1 h with horseradish peroxidase-conjugated goat anti-mouse or goat anti-rabbit antibodies (1:20,000, Kirkegaard & Perry Laboratories, Inc., Gaithersburg, MD). The blots were visualized using a chemiluminescence substrate (ECL, Bio-Rad, Hercules, CA), and the light images were collected and analyzed photometrically with a Fluor-S MultiImager and Quantity One software (Bio-Rad, Hercules, CA). For all Western blots, on each gel 2 or 3 lanes were reserved for a quality control (QC) sample. This sample was taken from a pool of a large number of hippocampal slices from naïve animals. Aliquots of the pool were maintained at 70°C. One aliquot was used for each gel or series of gels run at one time. After correction for background chemiluminescence, the signals from target bands on a gel were normalized to the average signal for the QC sample bands to simplify comparison across gels and reduce inter-gel variability. The coefficient of variation for the QC values across gels was typically below 10%.
To investigate phosphorylation of ERK, mouse monoclonal anti-phospho ERK1/ERK2 (diluted 1:2500, Cell Signaling, Beverly, MA) was used for the primary antibody incubation. Following visualization, the blots were stripped by incubation in stripping buffer (Restore, Pierce Chemical Co, Rockford IL) for 5 min, reblocked for 15 min with 5% nonfat dried milk at room temperature, then probed for total ERK using anti-total ERK1/ERK2 (diluted 1:5000, Cell Signaling, Beverly, MA). For each experiment, both total-ERK1 and total-ERK2 and phospho-ERK1 and phospho-ERK2 signals were normalized relative to those seen in unstimulated slices from the same animal. In addition, active ERK1 and ERK2 signals were normalized to total ERK1 and total ERK2 band intensities.
Rabbit polyclonal antibodies against synapsin (diluted 1:25000, Chemicon, Temecula, CA), and one recognizing a common site on both GAP-43 and RC3 (diluted 1:1000, Upstate, Lake Placid, NY) were used to probe for levels of these neuronal markers. For each blot, synapsin, GAP-43, and RC3 levels in the two PTU-exposed groups were normalized to QC standards and expressed as a percentage of the levels observed in control animals.
Thyroid hormones.
At the time of sacrifice for electrophysiological testing, trunk blood was collected and allowed to clot on ice for a minimum of 30 min. Serum was separated via centrifugation and stored at 80°C for later analyses by radioimmunoassay. Serum concentrations of total thyroxine (T4) and total triiodothyronine (T3) were analyzed by radioimmunoassay (Diagnostic Products Corp., Los Angeles, CA). Thyroid stimulating hormone (TSH) was measured using standard double antibody assay as described by Thibodeaux et al. (2003). All samples for total T4 and total T3 were run in duplicate and the intra- and interassay variations ranged from 9 to 12%. The minimum detectable concentration (MDC) for each assay was determined statistically (3 standard deviations above background levels). For all T3 assays (n = 4), the MDC was 7.8 ng/ml, and for the T4 assay (n = 4), the MDC was 4.9 ng/ml. The lowest calibrator for each assay was 10 ng/ml. For statistical purposes, in those cases where the sample result was below the level of this calibrator, the result was set by default to the MDC.
Statistical analysis.
Group statistics were calculated as the mean ± SEM. Data from electrophysiological studies were evaluated using repeated measures analysis of variance (ANOVA). Where significant interactions were found, step-down ANOVAs and mean contrast tests using Tukey's t-test were performed. Thyroid hormone data were evaluated using one-way ANOVAs. Protein data were evaluated using nonparametric chi-square analysis. Probabilities less than 0.05 were considered significant.
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Results |
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Dose-dependent reductions in thyroid hormones with concomitant elevations in TSH were observed in offspring at weaning and were reported in Sui and Gilbert (2003) and are summarized in Table 1. Dams displayed hypothyroxinemia at the low dose (reduced T4 with no significant reduction in T3), but hypothyroidism in the high-dose group (T3 and T4 reduced by 45 and 65%, respectively). Offspring were more severely affected; T4 in the low-dose group was reduced by 70% at weaning, and the majority of high dose animals fell below the level of detection of the assay. T3 was reduced by 35% and 70% in low and high dose animals, respectively. Although significant changes in thyroid hormones were observed in dams and young animals, complete recovery of T3 and T4 was evident in adult males at the time of testing (see Table 1). No significant differences were apparent in T4, T3, or TSH across dose groups (all p values > 0.1).
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Discussion |
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Less severe thyroid hormone reductions in the low-dose group were without impact on baseline measures of synaptic transmission, but did reduce paired-pulse facilitation of the EPSP area, augmented population spike LTP, and enhanced stimulation-induced phosphorylation of ERKs. These results indicate that long-lasting disruptions in hippocampal synaptic function remain following moderate thyroid hormone insufficiency during early brain development. Persistent perturbations in synaptic function and cell signaling may contribute to cognitive dysfunction in adult animals suffering from a temporary thyroid hormone insufficiency during critical periods of brain development (Akaike et al., 1991; Darbra et al., 2004
; Guadano-Ferrez et al., 2003
).
Previous studies have reported that synaptic proteins or mRNA levels of these proteins are altered by developmental (e.g., Iniguez et al., 1993, 1996
; Vara et al., 2002
; Wong and Leung, 2001
) and adult-onset hypothyroidism (Gerges and Alkadhi, 2004
; Iniguez et al., 1992
). Augmentation in basal levels of phosphorylated ERK was also recently reported in the hippocampus of newborn rat pups born to hypothyroid dams (Calloni et al., 2004
). In this study, the protein levels of synapsin, GAP-43, RC3, and basal levels of total or phosphorylated ERKs in area CA1 of rat hippocampus were not affected by prior PTU exposure. These findings indicate that recovery of these biochemical indices correlates with the animal's return to a euthyroid state. Thus, it is unlikely that the observed functional deficits are attributable to permanent reductions in the basal levels of these neurochemical substrates. Rather, we postulate that the interference with thyroid hormone regulation of the expression of these proteins induced by early hormonal insufficiencies resulted in subtle aberrations in synaptic structure, connectivity, and network wiring and is reflected in the persistent impairments in synaptic function observed in the adult.
We do not know what is responsible for the PTU-induced dissociation observed in LTP of the dendritic versus somatic cell region. This observation is consistent with previous reports from our laboratory in slices from adult animals exposed in a primarily postnatal hypothyroid paradigm (Gilbert, 2003), and in population spike LTP assessed in vivo in the dentate gyrus following recovery from developmental hypothyroidism (Gilbert and Paczkowski, 2003). It is unlikely that augmentations in population spike LTP are secondary to the observed enhancements in baseline synaptic transmission. Increases in population spike LTP of comparable magnitude were evident in both dose groups, whereas increased cell excitability as evidenced in input-output functions (Fig. 1) was limited to the high-dose group. Furthermore, EPSP-population spike coupling presented in Figure 2 revealed that, despite significant increases in these parameters in high-dose animals, a normal ratio between the two components of the synaptic field potentials was maintained. Collectively, these observations indicate that augmented LTP of the population spike is not a simple consequence of increased excitability, but reflects a change in the network response to activity-induced plasticity.
Subtle perturbations in synaptic architecture or expression and localization of receptor- and voltage-gated ion channels induced by thyroid hormone insufficiencies may account for augmented population spike LTP. Calcium influx through N-methyl-d-aspartate (NMDA) receptors localized on dendritic spines is critical for LTP induction of the EPSP (Bliss and Collingridge, 1993; Zador et al., 1990
). Voltage-dependent calcium channels (VDCC) localized on the cell soma and proximal dendrites mediate Ca2+ increases at the somatic level and contribute to synaptic plasticity of the population spike (Dudek and Fields, 2001
, 2002
; Muller and Connor, 1991
; Nicoll and Malenka, 1995
). Thus, differential expression or localization of NMDA and VDCC on pyramidal cell soma versus dendrites induced by inadequate hormone supplies during brain development may be reflected in an enhanced population spike LTP in the absence of changes in the dendritically-derived EPSP measure.
This hypothesis is consistent with our observations that developmental PTU treatment augments the phosphorylation of ERKs induced by LTP. Recent reports indicate that theta burst stimulation, as used in the present study, induces activation of the MAPK cascade and phosphorylation of ERK2 via calcium influx channels coupled to NMDA-receptors (Dudek and Fields, 2001). As is the case in the present study, LTP in slices from control animals was associated with phosphorylation of ERK2, with no change in ERK1 (Figs. 5B and 5C). However, calcium influx through L-type calcium channels in response to somatic action potentials and NMDA-receptor independent LTP are correlated with activation of ERK1 in addition to ERK2 (Aniksztejn and Ben-Ari, 1991
; Dudek and Fields, 2001
, 2002
; Kanterewicz et al., 2000
). Thus in the present study, the LTP-induced increase in phosphorylation of ERK2 above the levels achieved in controls, with the added phosphorylation of ERK1 that was restricted to PTU-exposed animals, is consistent with the observed augmentation in the amplitude of population spike LTP. As no difference in LTP magnitude was seen in the EPSP slope, it is tempting to speculate that augmented population spike LTP reflects enhanced calcium influx through L-type calcium channels at the cell soma in slices from developmentally thyroid-compromised animals.
The functional significance of enhanced LTP, protein phosphorylation, and perhaps ion channel properties to the behavior of the animal are unclear. Certainly the coordinated synchronization between synaptic depolarization and cell discharge, and the complex cell signaling pathways put into motion by activity-dependent synaptic plasticity in the hippocampus have been permanently disturbed as a consequence of early thyroid hormone insufficiency. This is likely to lead to information processing impairments within the hippocampal network and perhaps contribute to the learning deficits observed in animal models and subtle cognitive impairments in children suffering compromised thyroid status early in development.
In summary, the present study reported the persistent effects of moderate developmental thyroid hormone insufficiency on adult hippocampal synaptic functions. The degree of thyroid hormone suppression in treated dams at the time of weaning was indicative of hypothyroxinemia (i.e., no change in T3 but reduced T4 and concomitant rise in TSH). The perturbations in hippocampal synaptic function persist despite return to normal thyroid status. These observations replicate and expand upon recent work from our laboratory (Gilbert, 2004; Gilbert and Paczkowski, 2003
), but significantly extend the range of observation of functional deficits to levels of hormone disruption that do not impart significant toxicity to the dam or offspring (i.e., 3 ppm-dose group). In addition, results of neurochemical analyses reveal that the physiological perturbations in synaptic plasticity observed in the euthyroid adult animal are associated with alterations in MAPK signaling, and further implicate this signaling cascade in the neuropsychological impairments that accompany developmental thyroid hormone insufficiency.
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NOTES |
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ACKNOWLEDGMENTS |
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