* Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; and
Department of Psychology, University of North Carolina, Chapel Hill, North Carolina
Received February 25, 2000; accepted May 16, 2000
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ABSTRACT |
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Key Words: Aroclor 1254; Long-Evans rats; spatial learning; hippocampus; long-term potentiation (LTP); polychlorinated biphenyls (PCBs); rat; dentate gyrus.
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INTRODUCTION |
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The hippocampus has long been implicated in memory function in humans (Squire, 1992) and the rodent hippocampus has been considered to play an essential role in spatial learning (O'Keefe and Nadel, 1978
). Lesions and pharmacological interventions have been used to alter hippocampal function, and these manipulations result in impairments in working and reference memory as assessed in radial-arm maze and water-maze procedures (e.g., Morris, 1989; O'Keefe and Nadel, 1978; Squire, 1992; Steele and Morris, 1999). Hippocampal long-term potentiation (LTP) is a model of synaptic plasticity postulated to encompass the substrates of information storage at the synaptic level (Bliss and Collingridge, 1993
). Evidence that hippocampal glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype are critically involved in spatial learning tasks and LTP in area CA1 and dentate gyrus of the hippocampus supports the contention that hippocampal LTP represents the physiological basis of memory storage (Bannerman et al., 1995
; Davis et al., 1992
; Morris, 1989
; Morris et al., 1986
; Steele and Morris, 1999
; Tsien et al., 1996
).
A number of recent studies have reported deficits in tetanus-induced LTP in area CA1 of the dorsal hippocampus in response to acute in vitro exposure to some PCBs (Gilbert and Liang, 1998; Niemi et al, 1998
; Wong et al, 1997b
) but information on hippocampal dysfunction in animals developmentally exposed to PCBs is quite limited. Altmann et al. (1995, 1998) reported that LTP was not impaired in area CA1 of rat hippocampal slices but was reduced in visual cortex slices from animals exposed perinatally to a coplanar congener, PCB77 (3,3',4,4'-tetrachlorobiphenyl). Recently, we reported persistent impairment of LTP in a different hippocampal subregion (i.e., dentate gyrus) in animals exposed developmentally to A1254 (Gilbert and Crofton, 1999
). LTP was assessed in vivo in the offspring of dams exposed during gestation and lactation and reductions in the magnitude of dentate gyrus LTP were observed in the presence of only minimal effects in the baseline synaptic response profile. In this and the present study, the dentate gyrus was examined, as this is the site most readily accessible for in vivo study. Large field potentials are reliably evoked in the dentate gyrus in intact animals in response to perforant path stimulation, and long-lasting LTP can be readily induced (see Gilbert and Burdette, 1995). The present study attempted to expand upon our earlier work by assessing both LTP and spatial learning in PCB-exposed animals. Consistent with previous findings, we report a reduction in the magnitude of evoked LTP, but in this instance, no effects on baseline synaptic transmission were discerned. Furthermore, the current findings suggest that LTP deficits in PCB-exposed animals may be related to increases in the threshold for LTP induction. In the present study, however, we found no evidence of impaired spatial learning in the Morris water maze in animals developmentally treated with PCBs.
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MATERIALS AND METHODS |
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Behavioral testing.
Beginning on PND 90 (±5 days), one male and one female from 16 control and 15 PCB-exposed litters were tested for performance in the Morris water maze (Morris et al., 1986). Animals were placed in a quiet holding room adjacent to the test room for a minimum of 30 min prior to testing. The water maze consisted of a circular galvanized tank, with 148-cm diameter x 60-cm height. The pool was filled with tap water adjusted to 2325°C and made opaque by addition of nontoxic, water-soluble paint powder. The water level was set at a height of 0.40 m above the base. Four equally spaced locations around the edge of the pool were defined as start points, and divided the pool into 4 quadrants. A circular acrylic escape platform, 10 cm in diameter, was placed 1.5 cm beneath the water surface, in the middle of one of the 4 quadrants of the pool. The pool was placed in a 2.5 x 2.5 m square room, containing invariant spatial stimuli, including, a door, a black lab bench, and one storage cabinet. A video camera hanging from the ceiling allowed the observer to monitor the rats' behavior on a TV monitor placed in one corner of the room.
Water-maze acquisition.
Animals were tested for a total of 2 daily trials, 5 days/wk, for 20 days. Each trial was separated by approximately 35 min. Rats were placed in the water, facing the wall of the pool, and allowed 1 min to find the escape platform. On each day, the start points used for each trial varied in a pseudo-random sequence, such that no two trials on the same day commenced from the same start point. If the animal reached the escape platform within 60 s, the escape latency was recorded, and the rat allowed to rest on the platform for 10 s before removal. If subjects failed to locate the platform within 1 min, they were guided to it by the experimenter, allowed 10 s to rest upon it, and assigned a latency score of 60 s for that trial.
Quadrant test.
On the final day of acquisition, a quadrant preference test was given to the animals 2 h after completion of the second acquisition trial. For this test, the escape platform was removed from the pool, and the rats were allowed to swim freely for 1 min. The time spent in each quadrant of the pool was recorded as an index of spatial learning.
Cued test.
Approximately one h after completion of the quadrant test, animals were tested on a cued version of the task. The platform was located in a quadrant different from the training quadrant and a yellow glove (same as that used by the experimenter to remove animals from the tank) was suspended approximately 30 cm above the escape platform. The escape latency for one trial was used as an index of cued performance.
Swim speed.
One week following quadrant and cued testing, swim speed was assessed to test for potential motor differences between treatment groups. Animals were placed in a separate water maze located in a different laboratory and allowed to swim freely in the pool for 1 min with no escape platform present. Swim speed was calculated as cm/s averaged over the 1-min test interval by an automated tracking system (SRI Instruments, San Diego, CA).
Repeated acquisition task.
Two days after completion of acquisition testing, a subset of animals (one male and one female per litter from 8 control and 7 A1254-exposed litters) were tested on a repeated acquisition version of the water-maze task for 5 consecutive days. For this task the location of the escape platform was changed daily, but was constant within a given day. The animal was required to search the tank on Trial 1 to locate the platform and to return to that same location on Trial 2. Latencies to reach the platform were recorded for each of 2 daily trials. All other conditions were similar to those of the initial acquisition testing.
Electrophysiological testing.
Between 5 and 7 months of age, male offspring were anesthetized with urethane (12 gm/kg, ip), mounted in a stereotaxic frame, and prepared for electrophysiological testing. Body temperature was maintained at 37.5°C by placing the animals on a heating pad throughout testing. Sample sizes are indicated on the figures and represent animals from 8 control and 7 dosed litters. No more than 2 subjects from each litter are represented in any group. Bipolar twisted stainless steel wire electrodes (250 µm in diameter and insulated except for the cut tips), crimped onto gold-plated Amphenol pins, were lowered into the angular bundle of the perforant path according to flat skull stereotaxic coordinates (7.2 mm posterior to bregma, 4.1 mm lateral to the midline). A bipolar recording electrode with a 0.5-mm tip separation was lowered into the ipsilateral dentate gyrus 3.5 mm posterior to bregma and 22.2 mm lateral to the midline. Nominal depths for stimulating and recording electrodes were 2.2 and 3.5 mm below the dura, respectively, but optimal depth placement was achieved through electrophysiological monitoring of the response evoked in the dentate gyrus, following single pulse perforant path stimulation. Stimulation of the perforant path evokes a monosynaptic extracellular field potential that can be reliably recorded from electrodes placed in the hilar region of the dentate gyrus (Lomo, 1971). The field potential is comprised of an initial positive component, the excitatory postsynaptic potential (EPSP), and a negative compound action potential, the population spike (PS) (see sample waveforms in inset of Fig. 3
). Field potentials were scored by selecting 5 points on each averaged waveform as described by Gilbert and Burdette (1995). Briefly, the PS amplitude was calculated by taking the average of the 2 peak-to-peak amplitudes that comprise the negative-going potential. The slope of the rising phase of the EPSP was determined at a fixed interval beginning approximately 1.0 ms after response onset and at least 0.5 ms prior to PS onset.
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Upon stability, 10 stimulus intensities, ranging from subthreshold for elicitation of a PS to maximum PS amplitude, were selected for each rat to provide a normalized range of PS amplitudes. The maximum stimulus intensity delivered to any animal was 1500 µA and the maximum peak-to-peak response amplitude had to exceed 3 mV for the rat to be used in the study. A 10-sweep average at each of the 10 stimulus intensities was recorded at a frequency of 0.1 Hz. This stimulus-intensity profile typically ranged from 100 to 1500 µA and varied from animal to animal. No group differences in intensity profile were observed.
Train delivery.
Immediately following the collection of the pre-train I/O function, a 10-sweep pre-train baseline response was collected at a midrange stimulus intensity (probe stimulus). This probe stimulus was then used to assess the magnitude of synaptic potentiation 15 min following administration of each train set to establish the train intensity at which LTP was induced. Six sets of train stimuli were administered 15 min apart in an ascending intensity series (25, 50, 100, 150, 200, and 300 µA). Each train set consisted of three 4-pulse burst (400 Hz) pairs, with 200 ms between bursts, at each intensity; 10 s intervened between each burst pair within a given train intensity set, and train intensity was increased at 15-min intervals. A 10-sweep averaged evoked potential was collected at the probe stimulus intensity beginning 15 min after each train intensity step increase, and compared to the pre-train baseline population-response amplitude. Additional responses at the baseline probe intensity were collected 30 and 60 min after the final train, to monitor the stability of the LTP over a more protracted time period. One h after delivery of the final train, a post-train I/O function was collected. The criterion for LTP threshold was nominally defined as potentiation 50% maximal increase observed in control animals 15 min after the highest intensity train stimulus of 300 µA.
Statistical analyses.
Water-maze data were analyzed with ANOVAs and repeated measures ANOVAs where appropriate. For the initial acquisition task, time latency to locate the hidden platform was calculated for each daily session by averaging the latency of the 2 daily trials and combining daily session scores into 4 blocks of 5 sessions each. Since a male and female from the same litter were tested, gender was nested under litter (to control for possible "litter" effects). Latency data were analyzed using a repeated measures ANOVA with 1 between subject (treatment) and 3 within subject (test session, trial, quadrant) factors. Electrophysiological response amplitudes for EPSP slope and PS were normalized to the percent of maximal response observed in the pre-train I/O function. Pre- and post-train I/O functions in control and PCB-exposed animals were evaluated using a repeated-measures ANOVA with one between (Dose) and 2 within (Session and Stimulus Intensity) subject factors. As previous work has indicated a reduction in LTP following A1254 exposure (Gilbert and Crofton, 1999), one-tailed tests were utilized to evaluate electrophysiological endpoints. I/O difference scores were calculated by subtracting pre-train from post-train values for each subject to more clearly visualize the differences in LTP magnitude in control and PCB-exposed subjects and permit mean contrast tests at each stimulus intensity (Tukey, alpha set at p < 0.05). Responses evoked to the probe stimulus before and 15 min after each train were expressed as the percent increase over the pre-train probe stimulus amplitude and were assessed using a repeated-measures ANOVA with one between (Dose) and one within (Train Intensity) subjects factor. Mean contrast tests were performed using Tukey's t-test (alpha set at p < 0.05).
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RESULTS |
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Behavioral Results
Acquisition, as assessed by reductions in mean latency to locate the hidden platform, occurred in both groups over the course of the 20 days of testing [Session Block F(3,25) = 173.69; p < 0.0001]. However, the rate of acquisition did not differ between control and A1254-treated animals [all p's > 0.22]. Latency scores for males were shorter than for females across treatment groups and a significant main effect of Gender [F(1,27) = 7.38, p < 0.0113] was revealed. However, there were no significant interactions of Gender with Dose or Session Block (both p's > 0.05), so the data presented in Figure 1 represent the pooled values for males and females, collapsing across litter. The quadrant preference test at the end of acquisition demonstrated preference for the quadrant that had contained the platform in the previous 20 days of testing in both control and PCB-treated animals (see inset Fig. 1
). Analyses revealed a significant main effect of Quadrant (p < 0.0001) with no effect of Dose or any interaction of Dose with Quadrant (all p's > 0.05). Neither were group differences revealed at the end of training in the cued version of the task or in motor competence as assessed by swim speed (Fig. 1
, all p's > 0.05).
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Robust LTP was induced in control animals as evidenced by the upward and leftward shift of the post-train I/O functions for PS and EPSP slope (Figs. 3A and 3B). Developmental exposure to A1254 reduced the amplitude of PS potentiation (Fig. 3A
). Repeated-measures ANOVA revealed a significant main effect of Dose [F(1,18) = 3.88; p < 0.032] and a Dose x Session interaction [F(1,18) = 3.9; p < 0.031]. In addition, significant Dose x Intensity [F(9,162) = 4.59; p < 0.0001] and Dose x Session x Intensity [F(9, 162) = 2.32; p < 0.0001] interactions were observed. Results of the difference score analysis for PS amplitude are presented in 4A. Mean contrast tests revealed significantly greater differences in PS amplitudes in the controls, relative to the A1254-treated animals at the mid- to high-range of the stimulus intensity I/O profile.
Results of EPSP slope potentiation are presented in Figure 3B. As previously observed, the magnitude of LTP of the EPSP slope is smaller than that observed for PS in this type of field potential analysis (e.g., Gilbert et al., 1999a,b). A significant main effect of session [F(1,17) = 26.47, p < 0.0001] verified that increases in EPSP slope were attained following train stimulation. The absence of a significant main effect of Dose, or significant Dose x Session or Dose x Session x Intensity interactions (all p's > 0.15) indicates that EPSP slope potentiation was not significantly reduced by developmental exposure to A1254. Neither were statistically reliable differences observed between groups for EPSP slope in the difference-score analysis (Fig. 4B
).
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DISCUSSION |
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The mechanisms underlying PCB-induced neurotoxicity remain unknown. Deficits in hippocampal synaptic plasticity have been reported following acute in vitro exposure to PCBs (Gilbert and Liang, 1998; Neimi et al., 1998; Wong et al., 1997b
). In this and previous work from our laboratory (Gilbert and Crofton, 1999
), tissue levels of PCBs had returned to background levels at the time of testing (Takagi et al., 1986
). This result indicates that the acute impairment by PCBs on synaptic plasticity in vitro cannot be readily invoked to explain the deficits seen in the present study. Rather, impairments in hippocampal plasticity that persist to adulthood following developmental PCB exposure are likely due to perturbations in brain organization during ontogeny.
PCBs disrupt calcium-mediated signaling in vitro (Kodavanti et al., 1993, 1996
; Wong et al., 1997a
; Wong and Pessah, 1996
, 1997
). Recent data have confirmed results from in vitro studies that calcium serves as a primary regulator of axonal growth and migration during development in vivo (Gomez and Spitzer, 1999
). In addition, perturbation of steroid and thyroid hormones have been associated with PCB exposure in vivo (Abbott et al., 1994
; Goldey and Crofton, 1998
; Goldey et al., 1995
; MacLusky et al., 1998
; Morse et al., 1993
; 1996
) and in vitro (Johansson et al., 1998
; Safe et al., 1991
). Members of the steroid hormone superfamily exert considerable influence on brain organizational properties during hippocampal ontogeny (de Kloet et al., 1988
; Gould and Cameron, 1996
; Gould et al., 1991
; Porterfield, 1994
; Rami and Rabie, 1990
). It is conceivable that PCBs interfere with the complex hormonal and calcium-mediated signaling that occurs during critical periods of hippocampal development and permanently alter synaptic organization in this brain region. Deficits in synaptic plasticity that persist into adulthood may be one consequence of this disturbance in early brain development.
Apart from data generated from acute in vitro studies, limited information exists on the long-term consequences of developmental PCB exposure on brain function. Permanent hearing deficits have been reported in rats exposed to a similar regimen of A1254 (Goldey et al., 1995; Herr et al., 1996
). The present findings are also consistent with those previously reported from our laboratory on dentate gyrus LTP following developmental exposure to A1254 (Gilbert and Crofton, 1999
). Altmann et al. (1995, 1998) failed to find disruption of hippocampal LTP assessed ex vivo in area CA1 of hippocampal slices following developmental exposure to PCB47 (2,2',4,4'-tetrachlorobiphenyl) or PCB77 (3,3',4,4'-tetrachlorobiphenyl). Impaired synaptic plasticity was observed, however, in slices of visual cortex taken from the animals exposed to PCB77 (Altmann et al., 1995
, 1998
). The complex A1254 mixture employed in the present study contains a variety of PCB congeners, including both PCB47 and PCB77. The inconsistency between the present findings and those of Altmann et al. (1995, 1998) may derive from the combined action of the profile of congeners contained within the A1254 mixture, ex vivo vs. in vivo testing paradigms employed in the two laboratories, or CA1 vs. dentate gyrus as the site where plasticity was assessed. Although both dentate gyrus and area CA1 LTP are NMDA-dependent and appear to rely on similar biochemical substrates (Bliss and Collingridge, 1993
), both sites have distinct developmental profiles that may also contribute to selective vulnerability (see below).
The results of the behavioral studies are consistent with findings from our laboratory demonstrating detrimental effects of developmental lead exposure on hippocampal LTP in vivo (Gilbert et al., 1996; 1999a
,b
) in the absence of any discernible impairment in water maze learning (preliminary findings of Samsam and Gilbert, 1999). These observations contribute to a growing body of evidence demonstrating a dissociation between hippocampal LTP and learning/memory and have been argued by some to indicate the rather tenuous link between LTP and memory storage mechanisms (see review by Shors and Matzel, 1997). However, the position adopted by most skepticsthat there must be a one-to-one correspondence between LTP at a single synaptic locus and performance of a complex learning taskis untenable. The notion confuses synaptic with circuit levels of analysis in that LTP reflects the change in activity across a single synaptic site, whereas learning reflects the properties of an entire functional circuit. As such, activity at a single synapse is not a sufficient explanation of learning. The synaptic properties that make LTP a plausible mechanism for association formation need not be isometric with the properties of the entire behavioral system (for discussion see Barnes, 1995; Martinez and Derrick, 1996; Shors and Matzel, open peer commentary, 1997).
Recent evidence using selective gene deletions of NMDA-R1 receptor in area CA1 demonstrates that impaired LTP in area CA1 is coincident with impaired spatial learning in the water maze (Tsien et al, 1996). LTP in the dentate gyrus of these mutant mice, however, was normal. Conversely, mice lacking the gene encoding Thy-1, an adhesion cell molecule, demonstrate intact CA1 LTP and normal water-maze learning. These animals are deficient, however, in LTP in the dentate gyrus (Nosten-Bertrand et al., 1996
). Collectively, these data suggest that LTP in the CA1 region of hippocampus, but not the entorhinal projection to the dentate gyrus assessed in the present study, may be critical for water-maze learning. It is not known if a similar regional dissociation is evident in another commonly used test of spatial memory, the radial-arm maze, a task in which Roegge et al. (2000) have demonstrated impaired performance of A1254-exposed animals.
The dentate gyrus and CA1 subregions of the hippocampus also have distinct developmental profiles, CA1 developing primarily prenatally in rodents, the dentate gyrus maturing much later in the postnatal period (Bayer and Altman, 1974). Although A1254 was delivered during gestation and lactation, it is not known if synaptic plasticity in the CA1 region of the hippocampus would also have been affected by this exposure. A1254-induced hearing loss is produced following postnatal but not prenatal exposure, i.e., exposure occurring during the time of cochlear development was detrimental, that occurring prior to cochlear development was without effect (Crofton et al., 2000
). LTP deficits were not observed in area CA1 following pre- and postnatal exposure to PCB77 or PCB47 (Altmann et al.; 1995
1998
). Preliminary data from our laboratory also indicate intact LTP in area CA1 in slices from animals exposed to A1254 in the perinatal period (Liang and Gilbert, unpublished observations). These observations suggest that in rodents, brain regions that develop postnatally may be preferentially vulnerable to PCB exposure through the lactating dam. Alternatively, the toxicokinetics and toxicodynamics of in utero vs. lactational PCB exposure in rodents may contribute to selective periods of vulnerability. An evaluation of behavioral function and synaptic plasticity in both subregions of the hippocampus, when exposure is restricted to the pre- or postnatal period, may be a useful model to address this question of developmental periods of vulnerability to PCBs. If the integrity of synaptic plasticity in area CA1 remains intact following developmental PCB exposure, it may be sufficient to support spatial learning as assessed in standard water-maze procedures (see Tsien et al., 1996).
A number of other explanations are possible to account for the lack of effect on water maze performance despite clear deficits in hippocampal dentate gyrus LTP. For example, PCB-exposed animals may be utilizing strategies distinct from controls to solve the water maze task, or compensatory mechanisms, either physiological or behavioral, may offset impaired plasticity in specific neural circuits required for task performance. Moreover, it is also possible that the remaining plasticity in the hippocampal circuitry is sufficient to support the processing demands inherent in this simple version of water maze task. Increasing task demands or task sensitivity may suffice to unmask behavioral deficits reflective of impairment, but not complete blockade, of hippocampal plasticity. Previous work has demonstrated memory deficits associated with developmental exposure to specific PCB congeners (Schantz et al., 1995). A current report from that laboratory (see Roegge et al., 2000) also reveals impaired working and reference spatial learning in a 12-arm radial maze in similarly exposed animals. Differences in the visuospatial, associative, sensory, and motivational factors contributing to place learning in these two maze procedures may account for the apparent discrepancy in findings (see Hodges, 1996).
In summary, we have expanded upon our initial observations of impaired hippocampal function in PCB-exposed animals by demonstrating an increase in the threshold for LTP induction in the dentate gyrus. We have replicated our earlier findings of a reduced capacity to support synaptic plasticity, but unlike our previous report, we did not observe changes in baseline synaptic transmission. We failed to find evidence of impairment in spatial learning associated with deficits in hippocampal plasticity using the Morris water maze. However, more sophisticated tests of learning and memory that impose greater demands on the animal, or are more specific to dentate gyrus dysfunction, may be required to reveal deficits in behavioral performance that are coincident with a reduction but not complete obliteration of synaptic plasticity in this brain region. Deficits in hippocampal LTP that persist into adulthood, following exposure that is limited to the perinatal period, suggest that PCBs disrupt neuronal growth and organization during the period of rapid brain development. A reduced capacity to support synaptic plasticity may contribute to cognitive dysfunction associated with developmental PCB exposure in children.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at the Neurotoxicology Division (MD-74B), National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, 86 T.W. Alexander Dr., Research Triangle Park, NC 27711. Fax: (919) 541-4849. E-mail: gilbert.mary{at}epa.gov.
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