Thyroidectomy- And Ptu-Induced Hypothyroidism: Effect of L-Thyroxine on Suppression of Spatial and Non-Spatial Memory Related Signaling Molecules

doi:10.21203/rs.3.rs-372353/v1

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Thyroidectomy- And Ptu-Induced Hypothyroidism: Effect of L-Thyroxine on Suppression of Spatial and Non-Spatial Memory Related Signaling Molecules

https://doi.org/10.21203/rs.3.rs-372353/v1

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The calcium/calmodulin protein kinase II (CaMKII) signaling cascade is crucial for hippocampus-dependent learning and memory. In adult rats, Hypothyroidism impairs hippocampus-dependent learning and memory, which can be prevented by simple replacement therapy with L-thyroxine (thyroxine, T4) treatment. In this study, we compared animal models of hypothyroidism induced by thyroidectomy and treatment with propylthiouracil (PTU). Our findings show that thyroidectomy and PTU models are equally effective as indicated by the identical plasma levels of thyroid stimulating hormone (TSH) and T4. The two model produced identical degree of inhibition of synaptic plasticity as indicated by depression of LTP. We then investigated the effect of thyroidectomy hypothyroidism and thyroxine treatment on the underlying molecular mechanism of spatial and non-spatial types of memory. To generate spatial memory, we used training in the radial arm water maze (RAWM) where rats had to locate a hidden platform. For non-spatial memory, rats were trained to swim to a clearly visible platform in an open swim field. Western blot analysis of hippocampal area CA1 revealed that training, on both mazes, of control and thyroxine-treated hypothyroid rats produced significant increases in the P-CaMKII, PKCγ, calcineurin and calmodulin protein levels, but the training failed to induce such increases in untreated thyroidectomized rats. As expected, we show that thyroxine therapy prevented the deleterious effects of hypothyroidism at the molecular level.

Cellular & Molecular Neuroscience

Neurology

TSH

T4 thyroidectomy

PTU

CaMKII

PKCɣ

calmodulin

calcineurin

rat

LTP.

Adult-onset hypothyroidism impairs the CNS functions [1,2] through suppression of synaptic plasticity and impairment of learning and memory [3-9]. Untreated hypothyroidism shows symptoms of severe cognitive impairments including inability to focus, slow mentation, impaired short-term memory events and failure to analyze and comprehend difficult questions [1, 10-16]. Earlier studies of models of adult-onset hypothyroidism reported serious impairment of learning and memory; coupled with impairment of long-term potentiation (LTP) [3,4,7,17, 18] . These studies also established possible molecular deficits that may be responsible for this impairment [7,17,19]. In most of these studies, thyroidectomy was used to induce hypothyroidism. Possible shortcomings of this model can be complication of surgery and loss of parathyroid gland.

The drug 6-n-propyl-2-thiouracil (PTU) has been widely used in experimental animals to generate hypothyroidism animal model and clinically to treat patients with Graves' disease [20-22]. The drug is known to reduce circulating levels of T4 and T3 and to increase levels of thyroid-stimulating hormone (TSH) by inhibiting thyroperoxidase, which activates iodine [23,24]. The drug also inhibits deiodinase, which converts thyroxine (T4) to triiodothyronine (T3) in the liver [25]. PTU may interfere with the neuronal isoform of nitric oxide synthase (NOS), which may explain the drug’s effect on brain development and plasticity. The clinical use of PTU and other antithyroid drugs has the risk of side effects including oxidative stress damage of brain tissue [20,21,26-28]. PTU-induced hypothyroidism causes impairment of synaptic transmission in area CA1 in the hippocampus, leading to memory impairment [29-31].

Levothyroxine (thyroxine, T4) replacement therapy improves memory in hypothyroid subjects [11,32-34]. Yet, clinical reports are inconsistent as to whether the thyroid hormone replacement therapy results in full reversal of learning and memory impairment induced by hypothyroidism [12,13,35-40]. Whereas the neural manifestations of deficiency of thyroid hormone during the developmental stages have been well studied [e.g. 5], adult onset hypothyroidism has not been adequately investigated. We have previously shown that thyroxine replacement therapy reverses both E-LTP [17], and L-LTP [7] impairments in a rat model of hypothyroidism.

Calcium/calmodulin protein kinase II (CaMKII) is a quintessential molecule for hippocampus-dependent learning and memory. Activation of CaMKII is triggered by an increase in free intracellular calcium concentration, which activates phosphokinase C (PKCɣ) [41-45]. Active PKCɣ induces dissociation of calmodulin from neurogranin allowing the free calmodulin to activate CaMKII causing its autophosphorylation until deactivated by a phosphatase such as calcineurin [46,47].

In the present experiments we compared the effect of T4 treatment on thyroidectomy- and PTU-induced hypothyroidism. Then, we studied in the thyroidectomy model, the molecular changes in hippocampal area CA1 during both spatial and non-spatial memory acquisition and the impact of replacement therapy on the levels of CaMKII cascade signaling molecules.

All animal experiments were carried out in accordance with the NIH Guide for Care and Use of Laboratory Animals and approved by the University of Houston’s IACUC. Wistar rats (adult male weighing 230 to 280g; Harlan, Indianapolis, IN) were housed in Plexiglas cages (6 rats per cage])on a 12:12 h light/dark schedule (lights on at 7AM) at room temperature with adlibitum access to standard rodent chow and water. All rats were kept undisturbed for one week after arrival to allow acclimation.

Thyroidectomy hypothyroidism model:

Standard procedures were followed for thyroidectomy as described [7,48,49]. Surgery was carried out under general anesthesia: i.p. injection of a mixture of ketamine (100 mg/kg), xylazine (2.5 mg/kg) and acepromazine (2.5 mg/kg). Euthyroid (control) animals underwent sham surgical procedures without the removal of the thyroid gland. For at least one week after surgery, thyroidectomized and control rats were watched closely for possible complications. Experiments were conducted four weeks after thyroidectomy.

Propyl-2-thiouracil [PTU] hypothyroidism model

Rats were separated into three groups: sham [euthyroid control] group, hypothyroid group and PTU treated group. PTU was given in drinking water (0.05% w/v) for a total of five weeks before electrophysiological studies or blood sampling were performed.

Treatments groups

Three major treatment groups were designated: control, hypothyroid, and hypothyroid/thyroxine groups. The hypothyroid/thyroxine groups were treated with thyroxine (Sigma, St. Louis, MO), 20µg/kg/day for 4 weeks. The control and hypothyroid groups received the same volume of the vehicle (0.9% w/v NaCl; sc) for the same duration.

Within each of the three animal groups, rats were randomly assigned into two subgroups: the hidden (H) platform groups and the visible (V) platform groups. The spatial memory; hidden platform groups, including H-control, hypothyroid (H-Hypo) and hypothyroid/thyroxine (H-Hypo/T4) groups. Animals of these groups had to swim in the radial arm water maze (RAWM) and locate a platform, hidden 2 cm below water level, in a small room with dimmed lights. Distal extra-maze spatial orientation prompts were placed on the room walls around the maze. The non-spatial memory, visible platform groups, including V-control, hypothyroid (V-Hypo) and hypothyroid/thyroxine (V-Hypo/T4) groups where animals could swim towards a clearly visible (2 cm above water level) escape platform in an open (no radial arms) swim field.

Hidden platform: Spatial memory training in the radial arm water maze (RAWM)

The RAWM is a reliable model for testing hippocampus-dependent spatial learning and memory [50,51]. It contained six-swim lanes (arms) in a black circular water tub. Animals must locate a platform hidden 2 cm below the water level at the far end of one of the swim arms (designated: the “goal arm”). The goal arm must not be changed for a particular rat within the trial set. In the acquisition (learning) phase rats were subjected to eight sequential trials followed 30 minutes later by one short-term memory test. Each trial was started at different start arm than the preceding trial. For a particular rat, the start arm may be one of the six-swim lanes except the goal arm. In each trial, a rat was allowed a maximum of one minute to find the hidden platform. When on platform, the rat was permitted to stay for 15 seconds after which it would go to the next trial. If the rat did not find the platform within the 1 minute, it was manually steered toward the platform and left there for the usual 15 seconds. An error was scored if the rat entered a different arm than the goal arm,

Visible platform task: non-spatial memory training

Training in the visible platform is a non-spatial memory type of the water maze task intended to test the sensory, motoric and motivational facets of the task. In this task, no distal extra-maze cues were required as the animals would be able to see the escape platform. The same water tub, but with no swim arms, was used in the visible platform experiments. The platform used was the same one as in the hidden platform but was visibly elevated 2 cm above the water level. The same number of trials as in the hidden platform experiments was administered to rats in the visible platform experiments. The water temperature was the same (24±1 °C) in both types of experiments.

Hippocampus dissection and Immunoblotting:

Immediately after the 30 minutes memory test, animals were sacrificed and CA1 region of the hippocampi was dissected out and homogenized in a 200 ml buffered isotonic cocktail containing protease and phosphatase inhibitors as previously reported [52-54]. The total protein in the samples was estimated by microBCA assay kit (Pierce Chemical Rockford, IL0 and the samples were stored at -80° C. until processed.

The tissue samples were diluted with the buffer solution so as to contain 5 µg protein/20 ml and then boiled for 5 min. Then, each sample (containing 5 µg protein) was resolved in the 8-16% SDS-acrylamide gel and proteins on the gel were transferred to PVDF membrane. The blots were first incubated with a primary antibody. For phosphorylated calcium calmodulin kinase (P-CaMKII), we used a mouse monoclonal antibody 22B1 (anti-P-CaMKII; Affinity Bioreagent, Golden, CO) (1:1000 dilution), which recognizes CaMKII only when it is auto-phosphorylated at threonine 286. The antigen-antibody complexes were visualized with HPR-conjugated goat anti-mouse IgG using EC Chemiluminescence. Autoradiographs bands were generated, which were quantified by densitometry. The ratio of P-CaMKII band intensity to GAPDH band intensity was compared among the different groups. The same procedure was followed for the other molecules. For detection of total CaMKII, a rabbit polyclonal anti-CaMKII (1:1500 dilution; Santa Cruz Biotechnology, Inc. CA) was used, which binds equally well to the phosphorylated and the non-phosphorylated forms of CaMKII. PKCɣ was detected using a rabbit polyclonal anti-PKCɣ (1:3000 dilution; Santa Cruz Biotechnology, Inc. CA). Monoclonal mouse anti-calmodulin (1:500 dilution; Sigma ABI])was used to probe for calmodulin. Rabbit polyclonal anti-calcineurin antibody (1:1000 dilution; Affinity Research Products) was used to probe for calcineurin. Mouse polyclonal antibody glyceraldehyde phosphodehydrogenase (GAPDH; 1:10,000 dilution; Sigma ABI) was used as a loading control for all protein molecules.

Measuring Thyroid Stimulating Hormone and Thyroxine Blood Levels

Before sacrificing the animals, blood samples were collected to measure thyroxine (T4) and thyroid stimulating hormone (TSH) levels as described previously [17]. Blood samples were collected and rapidly centrifuged for 15 minutes at 14000 rpm. Serum samples were stored at -80 C° for later biochemical analysis. The radioimmunoassay kit (ICN Pharmaceuticals, Orangeburg, NY) and the rat Thyroid Stimulating Hormone (rTSH) enzyme immunoassay (BiotraK, Amersham Biosciences, NJ) were used to measure serum levels of total T4 and TSH respectively. All serum samples were run in triplicate.

Electrophysiologic Recording in the Hippocampus

Recording the population spike (pSpike) in area CA1 of the hippocampus was performed as described elsewhere [48]. Following anesthesia with urethane (1.2 gm/kg intraperitoneally), rats were positioned in a stereotaxic frame and holes were drilled in specific areas of the skull. A stimulating concentric bipolar electrode was positioned in area CA3 of the left hippocampus at an angle of 5° towards the midline to activate the Schaffer-commissarial collaterals nerves. A glass capillary recording electrode loaded with 1% fast green dye in 2 M NaCl was emplaced in the CA1 region of the right hippocampus to record the pSpike. Rat body temperature was maintained throughout all the procedure with a heating lamp. Stimulation of area CA3 in the left hippocampus was used to evoke LTP in the right hippocampal area CA1. Stimulus intensity, around 30% of the maximum response (by construction of input/output curve), was set to evoke test response. There was no significant difference in the current strength provided to the different rat groups. After stabilizing the rat for thirty minutes, high frequency stimulation (HFS) was used to induce LTP. Stimulus train of eight pulses (400 Hz) was applied every 10 sec for a period of 70 sec. The pSpike was recorded from area CA1 as previously described and LTP was measured for 1 h after HFS by giving a test stimulus every 30s [55].

Axoclamp 2A amplifier (Axon Instruments, Inc., Foster City, CA) was used to amplified record evoked pSpikes from area CA1 of the right hippocampus and the slope of fEPSP was measured from the pSpike. Computer-based stimulation and recording were accomplished by the use of pCLAMP 8.2 software and DigiData 1322A (Axon Instruments, Inc.). A single point in an experiment was determined by averaging 10 consecutive traces. The slope of the fEPSP measured synaptic plasticity, whereas pSpike amplitude served as a measure of neuronal excitability.

Statistical analysis:

GraphPad Prism 7.0 computer program was used to carried out all statistics. Comparisons were made using one-way ANOVA test followed by Tukey posttest. All values were represented as mean ± SEM. P values < 0.05 were considered significant.

Effect of thyroidectomy and PTU on rat body weight, T4 and TSH serum level

At the end of study, the body weight of rats increased in all groups. However, the body weight gain in the thyroidectomized and PTU groups was significantly lower (p value < 0.05) than that of the control/sham operated group (Control: 63.0%, TX: 19.5% and PTU: 17.7%).

Hypothyroidism induced by thyroidectomy or PTU was evaluated by measuring serum T4 and TSH levels. In the current study, thyroidectomy or administration of PTU resulted in equally significant reductions in T4 levels (Fig 1A) along with significant increases in TSH levels (Fig 1B) compared to the control/sham groups, confirming induction of hypothyroidism. In both models T4 levels were not totally suppressed, this can be due either to insufficient dose of PTU or incomplete removal of thyroid glands in thyroidectomy surgery.

Comparison of the effect of thyroidectomy and PTU on synaptic plasticity

Before induction of LTP by repetitive HFS, animals from the three groups had similar basal synaptic transmission as indicated by non-significant differences in pSpike and f-EPSP at baseline among the various groups. This suggests that basal synaptic transmission seems to be unaltered by thyroid hormone deficiency (Fig. 2 A and B).

Repetitive HFS of the Schaffer collaterals evoked LTP in the CA1 region as indicated by increases in the f-EPSP and pSpike amplitude in all the tested groups compared to the baseline at any given time. However, these values at all time points were significantly lower in both hypothyroid groups compared to the control/sham group (Fig. 2 A and B) The magnitudes of pSpike and f-EPSP in PTU and thyroidectomy groups, were generally not significantly different from each other, suggesting the induction of hypothyroidism in the two models caused comparable impairment of synaptic plasticity (Fig. 2 A and B).

Inasmuch as the two hypothyroid models produced nearly identical results in the levels of T4 and TSH as well as on synaptic plasticity, we decided to proceed with the thyroidectomy model only to look at spatial and non-spatial memory effects on the levels of memory related essential signaling molecules and test the efficacy of hormone replacement treatment in reversing the hypothyroidism-disrupted signaling cascade.

Spatial memory: the hidden platform task

In the 8 trials, all rats committed a high number of errors at the beginning of the trial set. However, while the H-control and H-Hypo/T4 rats had already located the hidden platform, the H-hypo group did significantly more errors than the other groups especially in trials 4 and 5 (Fig 3). It The H-Hypo group took more than 5 trials for to learn the location of the hidden platform, whereas H-control and H-Hypo/T4 rat groups learned to locate the hidden platform after only 3 trials. At the end of the eight trials, rats in all three groups learned to locate the hidden platform. This findings indicated that hypothyroidism delayed spatial learning, which was stopped by chronic treatment with thyroxine as seen in the performance of the H-Hypo/T4 (Fig. 3).

In the short-term memory test (30min after the last learning trial), the number of errors committed by the Hypo group was higher (P<0.01) than that made by H-control and H-Hypo/T4 groups (Fig. 3), where the H-Hypo/T4 rat group made a similar number of errors to that of the H-control rats. Thus, thyroxine treatment prevented hypothyroidism-induced spatial learning and short-term memory impairment.

Non-spatial memory: the visible platform task:

In this task, the rats showed normal speed and swimming form as well as normal impetus to swim. However, even though the hypothyroid animals showed no apparent impairment in the visible task performance, abnormal levels of memory related signaling molecules were detected in area CA1 of these hypothyroid rats (see below).

Thus, in both the hidden and visible platform tasks rats displayed similar motor, motivation, and sensory characteristics indicating that the impairments revealed in the hidden platform task may be due to a loss of ability to learn rapidly and remember appropriately.

Levels of signaling molecules

P-CaMKII: CaMKII is one of the most abundant proteins in the brain. It is a versatile enzyme that phosphorylates extensive range of substrates [56]. Memory formation stemming from training in the hidden platform maze produced significant surges in the levels of P-CaMKII in area CA1 of the hippocampus of control (H-Control), and H-Hypo/T4 rat groups. However, the protein levels of P-CaMKII in the hypothyroid rats of both the hidden and visible platform groups were not increased and were significantly less than levels of the H-Control, H-control and H-Hypo/T4 groups (Fig. 4A). Additionally, there was no significant difference in the levels of P-CaMKII molecule between the V-Hypo and H-Hypo groups (Fig. 4A). Thyroxine treatment (V-Hypo-T4) restored the level to that of V-control and that of H-Hypo-T4 to the level of H-control. Thus, hormone replacement treatment stopped the hypothyroidism-induced deficiency of the phosphorylation process.

Total CaMKII in all groups, the protein levels of total CaMKII were markedly higher in the hidden than those of the visible platform groups. Therefore, the lack of increase in the P-CaMKII level of the hypothyroid groups could be possibly largely due to impaired phosphorylation process.

PKCɣ,calmodulin and calcineurin: PKCɣ is essential for causing separation of calmodulin from the neurogranin-calmodulin complex, where the newly formed free calcium/calmodulin complex binds to and activates the enzyme CaMKII. In both V-Hypo and H-Hypo the protein levels of PKCɣ induced by learning and memory in the hypothyroid rat groups were significantly lower (p<0.05) than those of the corresponding control and H-Hypo/T4 groups. Thyroxine treatment in both groups restored the levels of PKCɣ (Fig. 5A).

In the hypothyroid groups, calmodulin protein levels of both V-Hypo and H-Hypo, although similar to each other, were significantly (p<0.05) lower than levels in the corresponding control and Hypo/T4 groups. There was no significant difference in the calmodulin levels between the hidden and visible platforms in the control as well as hypo/T4 groups (Fig. 5B).

Calcineurin (PP2B), a calcium and calmodulin dependent protein phosphatase that dephosphorylates P-CaMKII [57]. Calcineurin levels in both V-Hypo and H-Hypo, although similar to each other , they were significantly (p<0.05) higher than levels in the control and Hypo/T4 groups (Fig. 5C). Treatment with thyroxine completely reversed the effect of hypothyroidism in both H- and V-Hypo groups. Calcineurin protein levels were not significantly different in the in V- and H-controls (Fig. 5C). High calcineurin levels may be a key factor in the reduced phosphorylation of P-CaMKII seen in hypothyroid animals.

The long-term effects of untreated or ineffectively treated hypothyroidism include systemic and neurologic complications [58]. It is well-known that hypothyroidism has an unambiguous negative effect on cognitive abilities, including memory [59-61]. Two rat models of hypothyroidism have been commonly used to study hypothyroidism in animals: thyroidectomy and PTU administration. PTU is frequently used as first line therapy for hyperthyroidism [22]. In the present experiments we compared the magnitude of hypothyroidism in these two models by determining levels of the thyroid T4 and TSH and measuring the effects on LTP of hippocampal area CA1 in the two hypothyroidism models. Our data indicate that the two models produced nearly identical effects on T4 and TSH levels as well as on the magnitude of LTP.

Our results indicate that hypothyroidism produced in both models impairs memory equally effectively. This conclusion is based on two sets of data. The first was based on comparing the effects of the two models on LTP, the widely accepted correlate of memory. The current study showed that both hypothyroidism models produced nearly identical impairment of LTP in area CA1 of the hippocampus. The second set comes from earlier work from other laboratories as well as ours. For example, using the same protocols and methods, testing in the RAWM memory task showed that both thyroidectomy [7] and PTU [62] models of hypothyroidism caused nearly identical impairment of learning and short-term memory. We concluded that PTU administration-induced memory impairment comparable to that induced by thyroidectomy, probably through interfering with the LTP in the CA1 region of the hippocampus. These findings are consistent with other studies in literature where these two models induce hypothyroidism with comparable results [63,64].

It is interesting that the current findings revealed both spatial and non-spatial memory acquisition are equally negatively impacted at the molecular level. The paucity of adequate levels of available P-CaMKII suggested a defective phosphorylation process or enhanced dephosphorylation activity [7,17]. The high levels of the phosphatase calcineurin after both spatial and non-spatial trainings reported in the present experiments support enhanced dephosphorylation of P-CaMKII.

Elevation of intracellular calcium resulting from activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors [65] leads to activation of PKCɣ. Activated PKCɣ phosphorylates neurogranin causing separation of calmodulin from the neurogranin-calmodulin complex [66,67]. Autophosphorylation of CaMKII ensues when the newly formed calcium/calmodulin complex binds to and activates CaMKII [68]. As indicated by the present findings that in the euthyroid control rats, non-spatial memory requires considerably less P-CaMKII and PKCɣ (figure 4A, 5A) probably because the rat is using the visual pathway, which requires less of these molecules to form memory of the location of the visible platform in the maze. However, the hypothyroid rats showed equally similar failure to enhance P-CaMKII levels in both spatial and non-spatial types of memory. Therefore, the seemingly unimpaired ability of rats to locate the visible platform despite decreased levels of P-CaMKII, PKCɣ and calmodulin, may be largely due to the animal utilizing visual pathway.

In the euthyroid control animals, the present experiments show a clear dissimilarity of the effect of spatial and non-spatial memory training on the levels of P-CAMKII and PKCɣ molecules both of which are essential for the formation of memory. It is conceivable that the reduction of PKCɣ and calmodulin levels in hypothyroid rats after both spatial and non-spatial memory acquisition shown herein may result in decreased levels of P-CaMKII, thus contributing to the impairment of LTP and cognitive ability during hypothyroidism.

Our previous reports show that adult-onset hypothyroidism diminishes basal activity of P-CaMKII as well as the protein levels of P-CaMKII, total-CaMKII and calmodulin in area CA1 of the hippocampus [7,17], which may be explained by the reduced levels of upstream molecules such as calmodulin and PKCɣ [7].

Disruption of the CaMKII molecular cascade in hypothyroidism may be responsible for the impairment of learning and memory. Our results also emphasize the fundamental function of CaMKII in hippocampus-dependent learning and memory processes [41,44], and uphold previous observations [7]. The present results also emphasize the beneficial effect of thyroid hormone replacement therapy, even at the molecular level, in preventing hypothyroidism-induced impairment of CaMKII molecular cascade, which is critical for spatial and non-spatial forms of memory. Restoration of thyroxine levels is clearly enough to reverse the molecular and mental dysfunctions related to hypothyroidism.

Funding: Financial support for this project was provided by American Heart Association Texas Affiliate, and the University of Houston’s various research grants (SGP and GEAR).

Conflicts of interest/Competing interests: Both authors declare no conflict of interest.

Availability of data and material: All data from this work are available for examination.

Code availability: No codes.

Authors' contributions (optional: please review the submission guidelines from the journal whether statements are mandatory)

Ethics approval: All animal experiments were carried out in accordance with the NIH Guide for Care and Use of Laboratory Animals and approved by the University of Houston’s IACUC.

Consent to participate: Both authors have agreed to participate in these experiments

Consent for publication: Both authors agree to publish results of these experiments

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Thyroidectomy- And Ptu-Induced Hypothyroidism: Effect of L-Thyroxine on Suppression of Spatial and Non-Spatial Memory Related Signaling Molecules

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