Altered hippocampus synaptic function in selenoprotein P deficient mice
© Peters et al; licensee BioMed Central Ltd. 2006
Received: 08 August 2006
Accepted: 19 September 2006
Published: 19 September 2006
Selenium is an essential micronutrient that function through selenoproteins. Selenium deficiency results in lower concentrations of selenium and selenoproteins. The brain maintains it's selenium better than other tissues under low-selenium conditions. Recently, the selenium-containing protein selenoprotein P (Sepp) has been identified as a possible transporter of selenium. The targeted disruption of the selenoprotein P gene (Sepp1) results in decreased brain selenium concentration and neurological dysfunction, unless selenium intake is excessive However, the effect of selenoprotein P deficiency on the processes of memory formation and synaptic plasticity is unknown. In the present studies Sepp1(-/-) mice and wild type littermate controls (Sepp1(+/+)) fed a high-selenium diet (1 mg Se/kg) were used to characterize activity, motor coordination, and anxiety as well as hippocampus-dependent learning and memory. Normal associative learning, but disrupted spatial learning was observed in Sepp1(-/-) mice. In addition, severe alterations were observed in synaptic transmission, short-term plasticity and long-term potentiation in hippocampus area CA1 synapses of Sepp1(-/-) mice on a 1 mg Se/kg diet and Sepp1(+/+) mice fed a selenium-deficient (0 mg Se/kg) diet. Taken together, these data suggest that selenoprotein P is required for normal synaptic function, either through presence of the protein or delivery of required selenium to the CNS.
Selenium (Se) is a naturally occurring micronutrient that is essential for several known major metabolic pathways, including; thyroid hormone metabolism [1–3] and antioxidant defense systems [4, 5] in both humans and rodents. Dietary selenium can exist as selenomethionine, selenocysteine, selenate or selenite  and is incorporated as selenocysteine into a subset of specific selenium-dependent proteins (selenoproteins) . Of particular interest are the selenoproteins involved in oxidative stress, such as the glutathione peroxidase enzymes (classical GPX-1, gastrointestinal GPX-2, plasma GPX-3, phospholipid hydroperoxide GPX-4) and the thioredoxin reductase 1 and 2 (TR) [8, 9]. The dietary intake of selenium has a delicate balance between the harmful effects of excessive selenium uptake leading to selenium toxicity and the damaging effects on selenoprotein function during selenium deficiency. Interestingly, the CNS appears to be resistant to fluctuations in selenium and can maintain stable levels despite near complete depletion of dietary selenium uptake . This suggests that the process of selenium transport needed for selenocysteine-protein incorporation is important for normal CNS function.
Approximately 60% of selenium in plasma is present as selenoprotein P . This protein differs from other selenoproteins in that it incorporates up to 10 Se atoms per molecule in the form of selenocysteine as opposed to the single selenocysteine incorporated in other selenoproteins . Selenoprotein P is abundant throughout the body suggesting that one function is to serve as a primary transporter in systemic selenium delivery [13, 14]. This is especially evident in the CNS where selenoprotein P levels can be maintained independent of plasma selenium . However, genetic ablation of selenoprotein P results in reduced, but not a commensurate decrease in CNS-associated selenium levels, suggesting that other selenium proteins compensate for the selenoprotein P deficiency and supporting the hypothesis that basal selenium levels are essential for the brain and have a priority for available selenium [3, 16]. Sepp1(-/-) mice fed a selenium-deficient diet show severe motor dysfunction associated with neuron degeneration, which can be prevented by supplementation of high dietary selenium [16–18].
Reduced dietary selenium can have significant effects on levels of selenoproteins involved in oxidative stress, such as glutathione peroxidases, thioredoxin reductases and methionine sulfoxide reductases [19, 20]. Selenium, through the incorporation into selenoproteins, provides protection from reactive oxygen species (ROS)-induced cell damage . Because oxidative stress, and subsequent production of ROS, has been implicated in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Duchenne muscular dystrophy , there may also be a role for selenium in these disorders. In the present study we examined the consequences of selenoprotein P deficiency on cognitive capacity and synaptic function with a focus on the hippocampus, an area of the CNS intimately involved in learning and memory processes. Sepp1(-/-) mice demonstrate no overt behavior phenotype, but were found to have a subtle disruption in acquisition of spatial learning and memory. In contrast, synaptic transmission is altered and short- and long-term synaptic plasticity is severely disrupted in area CA1 of hippocampus. Interestingly, we found that when Sepp1(+/+) mice were fed a low Selenium diet (0 mg/kg), they too exhibited altered synaptic transmission and synaptic plasticity. Our observations suggest an important role for both selenoprotein P and dietary selenium in overall proper synaptic function.
Materials and methods
Littermates obtained from Sepp1(+/-) crosses were genotyped as described previously . This line has been back-crossed to C57BL6/J ten times. Animals were fed a Torula yeast-based diet supplemented with either 0 mg Se/kg or 1 mg Se/kg in the form of sodium selenite  and housed in a 10/14 hr light/dark cycle. Mice used for behavior were fed a diet of 1 mg Se/kg. Behavior testing was performed with 3–5 month old males and females during the light cycle. No gender-dependent differences were observed in any of the tests, therefore data were combined for graphical presentation and statistical analysis. All animal testing procedures were approved by the Institutional Animal Care and Use Committee of Vanderbilt University and followed the NIH guidelines for the care and use of laboratory animals.
Sepp1(-/-) and Sepp1(+/+) mice fed 1 mg Se/kg and Sepp1(+/+) mice fed 0 mg Se/kg were anesthetized by isofluorane and transcardially perfused with ice-cold clearing solution (0.1 M phosphate-buffered saline solution), followed by 4% paraformaldehyde (PFA) in 0.1 M phosphate buffer. Brains were then dissected, incubated overnight in 4% PFA at 4°C and cryoprotected with 30% sucrose. 40 μm coronal sections were cut using a cryostat (Leica CM 3050S) and mounted on gelatin-coated slides. Tissue was stained with 0.1% toludine blue to visualize the cellular structure of the hippocampus.
Starting speed for the rod began at 4 rpm and increased to 40 rpm over a 5 min period. Latency to fall was recorded as the time in which the mouse fell off the rod or failed to continue walking on the rod after two revolutions. The mice were given four trials per day with an inter-trial interval of 1 hour for two consecutive days. Data represent the mean ± SEM. Student's t test was used for statistical analysis with p < 0.05 as significance criteria.
Total distance traveled in the open field chamber (27 × 27 cm) during 15 min under standard room lighting conditions was assayed. Mouse activity was measured by 16 photoreceptor beams on all sides of the chamber connected to an Activity Monitor program (Med Associates, Inc). Zone analysis was performed to determine the time spent in the center of the chamber (designated by an 8 cm × 8 cm region) compared to the perimeter. Data represent the mean ± SEM. Student's t test was used for statistical analysis with p < 0.05 as significance criteria.
Elevated plus maze
The elevated plus maze apparatus consisted of two opposing open arms (30 cm × 5 cm) and two opposing closed arms (30 cm × 5 cm × 15 cm) connected by a central square platform and positioned 40 cm above the ground. Mice were placed in the open arms facing the closed arms at the beginning of the 5 min session. Data represent the total time spent in the various locations ± SEM. Student's t test was used for statistical analysis with p < 0.05 as significance criteria.
Training for contextual and cued fear conditioning consisted of a 2 min exploration period, followed by two conditioned stimulus (CS)-unconditioned stimulus (US) pairings separated by 90 sec (tone: 85 dB white noise, 30 s duration; foot shock intensity: 0.5 mA, 2 s duration). Context tests were performed in the conditioning chamber 2 hrs, 24 hrs, and 1 week post training. Cue tests were performed in a dissimilar chamber 2 and 24 hours post training; baseline freezing was monitored before presentation of the tone (85 dB white noise, 3 min duration). Freezing was defined as the absence of movement for 2 sec and measured objectively by a motion monitoring program (Med Associates, Inc). Data represent the mean ± SEM. Student's t test was used for statistical analysis with p < 0.05 as significance criteria.
Training for the hidden platform version of the Morris water maze consisted of four trials (60 s maximum; inter-trial interval, 60 min) each day with the starting location changing for each trial to avoid quadrant bias. On days 5, 7 and 10, a probe trial was administered before training by removing the platform and monitoring the animals' trajectory over 60 sec. The visible platform test was performed 2 hours after the last training session on day 10. A new platform was placed in the quadrant opposite from where they were trained. Above the submerged platform was a large red flag. The mice were placed in the opposite quadrant and latencies to find the new platform were recorded. Animal swim paths were objectively recorded with a video tracking system (HVS Image Analyzing VP-200). Data represent the mean ± SEM. Student's t test linear regression and χ2 tests were used for statistical analysis with p < 0.05 as significance criteria.
400 μm Hippocampus slices were prepared with a vibratome from 3–5 month old mice as described previously . Briefly, animals were sacrificed and brains were quickly placed in ice cold high sucrose cutting solution (in mM: 110 sucrose, 6 NaCl, 3 KCl, 26 NaHCO3, 1.25 NaH2PO4, 7 MgCl2, 0.5 CaCl2, 0.6 sodium ascorbate and 10 glucose, pH 7.3–7.4) and oxygenated with 95% O2/5% CO2. The hippocampus was dissected and allowed to equilibrate at RT in a 1:1 solution of cutting solution and artificial cerebrospinal fluid (ACSF: containing in mM: 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO3, 1.2 MgCl2, 2.0 CaCl2, and 10 glucose, pH 7.3–7.4) before recovering in oxygenated ACSF at 30°C in the interface recording chamber. All slices were permitted a minimum 1 hr recovery time before synaptic recording. Standard techniques as reported previously  were used to obtain extracellular field recordings and delivery of paired pulse and 100 Hz stimulations. Due to the high mortality of Sepp1(-/-) fed a selenium-deficient diet , Sepp1(-/-) mice used for electrophysiology were maintained on the high (1 mg Se/kg) selenium diet.
Normal hippocampal morphology in Sepp1(-/-) mice
Sepp1(-/-) mice show motor coordination defects but normal levels of locomotor activity and anxiety
Previous research of selenium deficiency in mice revealed reduced open field activity and that the mice spent less time in the center of the field indicating increased anxiety-like behavior . Thus, we performed the same open field test to assay general locomotor activity and anxiety. In comparing the total distance traveled during a 15 min exposure to the chamber we found no statistical difference between the Sepp1(-/-) mice and Sepp1(+/+) (Figure 2B). Zone analysis revealed that both genotypes spent equivalent amounts of time in the center of the chamber and the greatest amount of time in the surrounding areas, nearest to the walls of the chamber (Figure 2C). These results indicate that, unlike dietary selenium deficiency, the Sepp1(-/-) mice have normal exploratory tendencies and behave similar to their littermate controls when introduced to a novel open field.
A more sensitive analysis of anxiety can be achieved with the elevated plus maze. Both genotypes demonstrated a similar pattern of behavior when presented with the elevated plus maze. Equivalent amounts of time were spent in the open arms of the maze with the preponderance of time spent in the closed arms (Figure 2D). These observations are consistent with the open field analysis and suggest that genetic elimination of selenoprotein P does not have an adverse effect on overall anxiety-like behavior.
Sepp1(-/-) mice exhibit normal associative fear learning and impaired spatial learning
Sepp1(-/-) mice exhibit altered basal synaptic transmission and short-term plasticity in area CA1 of the hippocampus
The enhanced basal synaptic transmission suggests that synapses in Sepp1(-/-) mice might have an improved ability to undergo synaptic plasticity. Paired-pulse facilitation (PPF) is a form of short-term plasticity. When two pulses at a short interpulse interval are given to the afferent pathway, the postsynaptic response to the second stimulus is increased when compared with the first response. This phenomenon is understood to be due to residual calcium in the presynaptic terminal that facilitates neurotransmitter release upon the second stimulation resulting in the subsequent increase in the post synaptic response . We tested PPF by delivering paired stimuli at intervals ranging from 20 to 300 ms apart. The Sepp1(-/-) slices showed significantly reduced facilitation to the paired-pulse stimulation at intervals of 20, 40 and 120 ms (Figure 5C). Taken together with the input-output relationship data, these results suggest that changes in both presynaptic (altered neurotransmitter release) and postsynaptic properties (enhancement of fEPSP slopes) result from a loss of selenoprotein P.
A type of long-term plasticity exhibited by the Schaffer collateral-CA1 pathway is long-term potentiation (LTP). Two trains of high frequency stimulation (HFS: 100 Hz, 1 sec) spaced 20 s apart faithfully induces LTP in slices obtained from wild type mice characterized by a transient and highly robust post-tetanic increase in the slope of the fEPSP that is followed by a sustained and less robust increase (Figure 5D). Surprisingly, we found that this stimulation paradigm failed to elicit LTP in the Sepp1(-/-) slices. Strikingly, not even a modest transient post-tetanic increase was observed. In fact, we observed the opposite; Sepp1(-/-) slices responded to the HFS with a robust transient depression of the fEPSP slope (Figure 5D). We performed multiple HFS (2 trains of 100 Hz stimulation, separated by 20 sec repeated 4 times with each pairing given 5 minutes apart) on Sepp1(-/-) slices to determine if a stimulation threshold was preventing LTP induction. We found that this HFS protocol did not induce potentiation greater than our standard two train 100 Hz protocol (data not shown). This suggests that the LTP deficit in Sepp1(-/-) mice is independent of the amount of HFS presynaptic input, but does not rule out the possibility of occluded LTP.
Sepp1(+/+) mice feed a selenium deficient diet recapitulate the Sepp(-/-) phenotype
The similarity we saw between Sepp1(-/-) mice and Sepp1(+/+) 0Se mice in enhanced basal synaptic transmission does not extend to pre-synaptic testing by paired-pulse facilitation. Unlike the Sepp1(-/-) slices, the Sepp1(+/+) slices, regardless of diet, exhibit normal PPF at all interpulse intervals (Figure 6C). Taken together with the previous observation that Sepp1(-/-) slices exhibit reduced PPF, these results suggest that the absence of selenoprotein P during development may account for the defect in PPF.
LTP also is altered in slices obtained from Sepp1(+/+) 0Se mice. Similar to the Sepp1(-/-) slices, Sepp1(+/+) 0Se slices do not exhibit LTP in response to HFS. However, unlike the Sepp1(-/-) slices, Sepp1(+/+) 0Se slices do not respond to HFS with a robust transient depression of the fEPSP slope (Figure 6D), suggesting that the combination of presynaptic and postsynaptic dysfunction in Sepp1(-/-) mice may underlie their significant post-tetanic depression. Moreover, this observation paired with the PPF data suggests that a chronic reduction in selenium during adulthood does not recapitulate completely the alterations in synaptic function that result from genetic abolition of selenoprotein P.
The exact role(s) of selenoprotein P in tissues throughout the body are unknown, but since its discovery in 1977 several unique characteristics of the protein have been identified (for review see ). First, selenoprotein P incorporates 10 selenocysteine residues in the primary protein . In contrast, other identified selenoproteins exist with the incorporation of a single selenocysteine. Second, selenoprotein P is an abundant plasma protein found to be made in most tissues [13, 14]. High concentrations of selenoprotein P mRNA are in the liver, and the liver secretes selenoprotein P into plasma and interstitial fluid . Finally, selenoprotein P contains two distinct protein domains. The first domain consists of the N-terminal domain residue up to just before the second incorporated selenocysteine (AA 1–240). This domain contains a heparin binding motif and exhibits modest peroxidase activity [30–32]. The second domain extends from the second selenocysteine to the remaining protein and contains the other ~nine selenocysteines. Taken together, this suggests that selenoprotein P serves the essential role of transporting necessary selenium to other tissues in the form of selenocysteine, while maintaining a distinct domain that may serve in tissue-specific targeting, in particular the CNS.
Interestingly, dietary Se restriction of Sepp1(-/-) mice maintains relatively high concentrations of selenium in the CNS (Sepp1(-/-) 86 ± 12 ng Se/g, Sepp1(+/+) 99 ± 27 ng Se/g) compared to other tissues that often show 50–90% reduction in Se content (kidney, testis, liver) . Thus, the CNS appears to demonstrate a priority for selenium that goes beyond the capability for selenoprotein P-dependent selenium delivery. Furthermore, Se deficiency induced through dietary restrictions results in disruption of motor function and memory formation [16, 25], but these observation may be a result of neuronal cell death in the CNS. Thus, the present studies were performed in order to better define the contribution of selenoprotein P to synaptic function beyond selenium delivery .
We find distinct behavioral phenotypic similarities and differences between Sepp1(-/-) mice and selenium deficiency. For example, Sepp1(-/-) show normal overall activity and no change in anxiety. In contrast, selenium deficiency in mice have reported decreased activity in the open field test and increased anxiety demonstrated as decreased entry to the center of the field . This suggests that cerebellar function is especially sensitive to reduced selenium, which is supported by the deficit in balance and coordination determined by the cerebellum-dependant rotorod test. Spatial learning assessed with the Morris hidden platform test is disrupted in both Sepp1(-/-) mice and selenium-deficient mice, although the deficit in Sepp1(-/-) mice is subtle and can be overcome with continued training. The increased latency time for days 3, 4 and 6 suggest a learning deficit in acquisition, but the lack of a defect following the probe tests on day 5 suggests that the retention of memories once formed are unaffected. The subtlety of this learning deficit is more apparent in light of normal associative fear conditioned learning in Sepp1(-/-) mice compared to Sepp1(+/+).
Seeing no abnormal phenotype for the hippocampal-dependant fear conditioning test, we did not expect to see any unusual electrophysiology results. However, the most surprising results of these studies were seen in the electrophysiologic characterization of synaptic function in area CA1 in the hippocampus. Sepp1(-/-) mice show a significantly higher output with a given stimulus compared to Sepp1(+/+). The increase in the slope of the fEPSP at a given stimulus without a change in the fiber volley amplitude suggests that the defect may reside with postsynaptic function. This is supported by the severe deficit of LTP in Sepp1(-/-) mice, which is a predominately postsynaptic-dependent phenomenon. However, decreased PPF at short interpulse intervals is characteristic of presynaptic dysfunction. Interestingly, our results from Sepp1(+/+) mice on a 0 mg Se/kg diet show altered synaptic transmission and reduced LTP similar to that of Sepp1(-/-) mice. Thus, it is likely that selenoprotein P deficiency has no deleterious developmental consequences, but reductions in selenium, whether through the disruption of selenoprotein P gene or dietary selenium restriction, results in discernable differences in synaptic function. Regardless, it is interesting that these mice exhibit a very severe defect in synaptic plasticity across Schaffer collateral synapses of the hippocampus, yet show only subtle defects in the Morris hidden platform water test and normal associative fear conditioned learning, two distinct hippocampus-dependent behavioral processes.
What might be the mechanism underlying the changes in synaptic function? We can speculate on at least three putative scenarios. First, absence of selenoprotein P may result in diminished anti-oxidant capacity resulting in reduced LTP and disruption of presynaptic responses. However, most research shows that inhibition of antioxidants leads to profound memory disruption as well as disruption of LTP [33, 34], a phenotype we don't see in our Sepp1(-/-) mice. Second, the reduced selenium content in the CNS may be disrupting the specific function of a selenoprotein involved in synaptic plasticity. Homology studies have identified a number of selenium containing proteins, but none of these are obvious candidates as plasticity proteins. Finally, selenoprotein P may be acting as a signaling molecule through an as yet undetermined receptor. Receptor-dependent endocytosis of selenoprotein P would be a likely mechanism for selenium delivery to cells of the CNS. Numerous signal transduction pathways intimately involved in synaptic plasticity and learning and memory rely on ligand-induced endocytosed receptors [35–37]. Selenoprotein P deficiency, through direct or indirect interactions, may impact an important signaling system.
The present studies establish that selenoprotein P deficiency results in subtle spatial learning deficits and severe synaptic plasticity defects. It is difficult to discern whether this is due to selenoprotein P itself, or the loss of selenium transport to the CNS. However, the use of adult Sepp1(+/+) mice maintained on a 0 mg Se/kg diet suggests that the predominance of synaptic dysfunction in Sepp1(-/-) mice is not a result of developmental abnormalities. Future studies will help define whether selenoprotein P is acting as a signaling molecule in the CNS or simply facilitates the systemic distribution of necessary selenium.
- Sepp1 :
Selenoprotein P gene
High Frequency Stimulation
This work was supported by NIH grant ES02497 (R.F.B.), and NIA grant AG22574-01A1 (E.J.W.). We thank Dr. Jessica Banko for help in manuscript preparation/data analysis, and Jennifer Smith and Lori Austin for their expertise in husbandry, genotyping and careful dietary manipulation of the mice used in these studies.
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