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Comparison of Effects of Spatial and Non-Spatial Memory Acquisition on the CaMKII Pathway During Hypothyroidism and Nicotine Treatment

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Abstract

Molecular, cellular, and behavioral studies have shown that hypothyroidism impairs hippocampus-dependent learning and memory in adult rats. In these studies, spatial learning and memory were tested in the radial arm water maze (RAWM), which involved locating a hidden platform. In the present study, we investigated the effects of nicotine and hypothyroidism on the CaMKII pathway during learning and memory processes in both spatial and non-spatial memory forms. We used nicotine as a neuroprotective agent. Hypothyroidism was induced by thyroidectomy in adult rats. Rats were trained on the hidden platform (the RAWM for spatial learning and memory) and compared with age-matched rats that were trained on a clearly visible platform system (2 cm above water with no radial arms for non-spatial learning and memory). Nicotine (1 mg/kg twice/day) was administered subcutaneously for 4 weeks. Immediately after training, the protein levels of memory-related signaling molecules were determined in hippocampal area CA1. Western blot analysis revealed a significant increase in calcineurin levels and decreases in P-CaMKII, PKCγ, and calmodulin protein levels in area CA1 of the hippocampi of hypothyroid rats trained on both the visible and hidden platforms. Nicotine treatment normalizes these levels in hypothyroid rats trained on both the visible and hidden platforms. The results suggest that chronic nicotine treatment prevents hypothyroidism-induced suppression of the CaMKII pathway after spatial and non-spatial learning and memory.

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References

  1. Yin JJ, Liao LM, Luo DX, Xu K, Ma SH, Wang ZX, Le HB, Huang RR et al (2013) Spatial working memory impairment in subclinical hypothyroidism: an FMRI study. Neuroendocrinology 97:260–270

    CAS  PubMed  Google Scholar 

  2. Javed Z, Sathyapalan T (2016) Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Ther Adv Endocrinol Metab 7:12–23

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pasqualetti G, Caraccio N, Dell Agnello U, Monzani F (2016) Cognitive function and the ageing process: the peculiar role of mild thyroid failure. Recent Pat Endocr Metab Immune Drug Discov 10:4–10

    CAS  PubMed  Google Scholar 

  4. Gerges NZ, Alzoubi KH, Park CR, Diamond DM, Alkadhi KA (2004) Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats. Behav Brain Res 155:77–84

    PubMed  Google Scholar 

  5. Alzoubi KH, Gerges NZ, Alkadhi KA (2005) Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies. Exp Neurol 195:330–341

    CAS  PubMed  Google Scholar 

  6. Alzoubi KH, Aleisa AM, Gerges NZ, Alkadhi KA (2006b) Nicotine reverses adult-onset hypothyroidism-induced impairment of learning and memory: behavioral and electrophysiological studies. J Neurosci Res 84:944–953

    CAS  PubMed  Google Scholar 

  7. Tong H, Chen GH, Liu RY, Zhou JN (2007) Age-related learning and memory impairments in adult-onset hypothyroidism in Kunming mice. Physiol Behav 91:290–298

    CAS  PubMed  Google Scholar 

  8. Alzoubi KH, Gerges NZ, Aleisa AM, Alkadhi KA (2009) Levothyroxin restores hypothyroidism-induced impairment of hippocampus-dependent learning and memory: behavioral, electrophysiological, and molecular studies. Hippocampus 19:66–78

    CAS  PubMed  Google Scholar 

  9. Alzoubi KH, Alkadhi KA (2014a) Chronic nicotine treatment reverses hypothyroidism-induced impairment of L-LTP induction phase: critical role of CREB. Mol Neurobiol 49:1245–1255

    CAS  PubMed  Google Scholar 

  10. Alzoubi KH, Alkadhi KA (2014b) Levothyroxin replacement therapy restores hypothyroidism induced impairment of L-LTP induction: critical role of CREB. Brain Res Bull 100:29–37

    CAS  PubMed  Google Scholar 

  11. Gerges NZ, Alkadhi KA (2004) Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement. Hippocampus 14:40–45

    CAS  PubMed  Google Scholar 

  12. Aleisa AM, Alzoubi KH, Gerges NZ, Alkadhi KA (2005) Nicotine blocks stress-induced impairment of spatial memory and long-term potentiation of the hippocampal CA1 region. Int J Neuropsychopharmacol 9:417–426 1–10

    PubMed  Google Scholar 

  13. Alzoubi KH, Aleisa AM, Alkadhi KA (2008) The sliding threshold of modification hypothesis: application to the effect of hypothyroidism or chronic psychosocial stress and nicotine on synaptic plasticity. Neurosci Lett 430:203–206

    CAS  PubMed  Google Scholar 

  14. Newhouse PA, Potter A, Kelton M, Corwin J (2001) Nicotinic treatment of Alzheimer’s disease. Biol Psychiatry 49:268–278

    CAS  PubMed  Google Scholar 

  15. Tran TT, Srivareerat M, Alkadhi KA (2010) Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of Alzheimer’s disease. Neurobiol Dis 37:756–763

    CAS  PubMed  Google Scholar 

  16. Alkadhi KA, Alzoubi KH, Srivareerat M, Tran TT (2011) Chronic psychosocial stress exacerbates impairment of synaptic plasticity in beta-amyloid rat model of Alzheimer’s disease: prevention by nicotine. Curr Alzheimer Res 8:718–731

    CAS  PubMed  Google Scholar 

  17. Srivareerat M, Tran TT, Salim S, Aleisa AM, Alkadhi KA (2011) Chronic nicotine restores normal Abeta levels and prevents short-term memory and E-LTP impairment in Abeta rat model of Alzheimer’s disease. Neurobiol Aging 32:834–844

    CAS  PubMed  Google Scholar 

  18. Alzoubi KH, Aleisa AM, Alkadhi KA (2006a) Molecular studies on the protective effect of nicotine in adult-onset hypothyroidism-induced impairment of long-term potentiation. Hippocampus 16:861–874

    CAS  PubMed  Google Scholar 

  19. Oliva CA, Vargas JY, Inestrosa NC (2013) Wnt signaling: role in LTP, neural networks and memory. Ageing Res Rev 12:786–800

    CAS  PubMed  Google Scholar 

  20. Alzoubi KH, Aleisa AM, Alkadhi KA (2007) Nicotine prevents disruption of the late phase LTP-related molecular cascade in adult-onset hypothyroidism. Hippocampus 17:654–664

    CAS  PubMed  Google Scholar 

  21. Alzoubi KH, Alkadhi KA (2007) A critical role of CREB in the impairment of late-phase LTP by adult onset hypothyroidism. Exp Neurol 203:63–71

    CAS  PubMed  Google Scholar 

  22. Aleisa AM, Alzoubi KH, Alkadhi KA (2011a) Post-learning REM sleep deprivation impairs long-term memory: reversal by acute nicotine treatment. Neurosci Lett 499:28–31

    CAS  PubMed  Google Scholar 

  23. Khabour OF, Alzoubi KH, Alomari MA, Alzubi MA (2013) Changes in spatial memory and BDNF expression to simultaneous dietary restriction and forced exercise. Brain Res Bull 90:19–24

    CAS  PubMed  Google Scholar 

  24. Mhaidat NM, Alzoubi KH, Khabour OF, Tashtoush NH, Banihani SA, Abdul-razzak KK (2015) Exploring the effect of vitamin C on sleep deprivation induced memory impairment. Brain Res Bull 113:41–47

    CAS  PubMed  Google Scholar 

  25. Alzoubi KH, Rababa'h AM, Owaisi A, Khabour OF (2017) L-Carnitine prevents memory impairment induced by chronic REM-sleep deprivation. Brain Res Bull 131:176–182

    CAS  PubMed  Google Scholar 

  26. Rababa'h AM, Alzoubi KH, Atmeh A (2017) Levosimendan enhances memory through antioxidant effect in rat model: behavioral and molecular study. Behav Pharmacol 29:344–350

    Google Scholar 

  27. Alzoubi KH, Khabour OF, Ahmed M (2018a) Pentoxifylline prevents post-traumatic stress disorder induced memory impairment. Brain Res Bull 139:263–268

    CAS  PubMed  Google Scholar 

  28. Alzoubi KH, Khabour OF, Alharahshah EA, Alhashimi FH, Shihadeh A, Eissenberg T (2015) The effect of waterpipe tobacco smoke exposure on learning and memory functions in the rat model. J Mol Neurosci 57:249–256

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Al-Sawalha N, Alzoubi K, Khabour O, Alyacoub W, Almahmmod Y, Eissenberg T (2018) Effect of prenatal exposure to waterpipe tobacco smoke on learning and memory of adult offspring rats. Nicotine Tob Res 20:508–514

    CAS  PubMed  Google Scholar 

  30. Alzoubi KH, Mayyas FA, Mahafzah R, Khabour OF (2018b) Melatonin prevents memory impairment induced by high-fat diet: role of oxidative stress. Behav Brain Res 336:93–98

    CAS  PubMed  Google Scholar 

  31. Chavanne D, Constans T, Petit A, Mondon K, Hommet C (2011) Hypothyroidism and cognition in the elderly. Geriatr Psychol Neuropsychiatr Vieil 9:477–489

    PubMed  Google Scholar 

  32. Pasqualetti G, Pagano G, Rengo G, Ferrara N, Monzani F (2015) Subclinical hypothyroidism and cognitive impairment: systematic review and meta-analysis. J Clin Endocrinol Metab 100:4240–4248

    CAS  PubMed  Google Scholar 

  33. Gerges NZ, Alzoubi KH, Alkadhi KA (2005) Role of phosphorylated CaMKII and calcineurin in the differential effect of hypothyroidism on LTP of CA1 and dentate gyrus. Hippocampus 15:480–490

    CAS  PubMed  Google Scholar 

  34. Fukunaga K (1993) The role of Ca2+/calmodulin-dependent protein kinase II in the cellular signal transduction. Nippon Yakurigaku Zasshi 102:355–369

    CAS  PubMed  Google Scholar 

  35. Feng TP (1995) The involvement of PKC and multifunctional CaM kinase II of the postsynaptic neuron in induction and maintenance of long-term potentiation. Prog Brain Res 105:55–63

    CAS  PubMed  Google Scholar 

  36. Kim JJ, Yoon KS (1998) Stress: metaplastic effects in the hippocampus. Trends Neurosci 21:505–509

    CAS  PubMed  Google Scholar 

  37. Wang JH, Kelly PT (1995) Postsynaptic injection of CA2þ/CaM induces synaptic potentiation requiring CaMKII and PKC activity. Neuron 15:443–452

    PubMed  Google Scholar 

  38. Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN (1989) An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340:554–557

    CAS  PubMed  Google Scholar 

  39. Giese KP, Fedorov NB, Filipkowski RK, Silva AJ (1998) Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279:870–873

    CAS  PubMed  Google Scholar 

  40. White HK, Levin ED (2004) Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment. Psychopharmacology 171:465–471

    CAS  PubMed  Google Scholar 

  41. Aleisa AM, Helal G, Alhaider IA, Alzoubi KH, Srivareerat M, Tran TT, Al-Rejaie SS, Alkadhi KA (2011b) Acute nicotine treatment prevents REM sleep deprivation-induced learning and memory impairment in rat. Hippocampus 21:899–909

    CAS  PubMed  Google Scholar 

  42. Alzoubi KH, Khabour OF, Salah HA, Abu Rashid BE (2013) The combined effect of sleep deprivation and Western diet on spatial learning and memory: role of BDNF and oxidative stress. J Mol Neurosci 50:124–133

    CAS  PubMed  Google Scholar 

  43. Levin ED (2013) Complex relationships of nicotinic receptor actions and cognitive functions. Biochem Pharmacol 86:1145–1152

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Rezvani AH, Eddins D, Slade S, Hampton DS, Christopher NC, Petro A, Horton K, Johnson M et al (2008) Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: persisting effects on locomotor activity, learning and nicotine self-administration. Neuroscience 154:885–897

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Barreto GE, Iarkov A, Moran VE (2014) Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease. Front Aging Neurosci 6:340

    PubMed  Google Scholar 

  46. Alkadhi KA (2018) Neuroprotective effects of nicotine on hippocampal long-term potentiation in brain disorders. J Pharmacol Exp Ther 366(3):498–508

    PubMed  Google Scholar 

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Funding

Financial support for this project was provided by the University of Houston, TX, USA (SGP and GEAR), and the Deanship of Research at Jordan University of Science and Technology, Jordan (grant number 364/2015).

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  1. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204-5515, USA

    K. A. Alkadhi

  2. Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

    K. H. Alzoubi

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Correspondence to K. A. Alkadhi.

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Alkadhi, K.A., Alzoubi, K.H. Comparison of Effects of Spatial and Non-Spatial Memory Acquisition on the CaMKII Pathway During Hypothyroidism and Nicotine Treatment. Mol Neurobiol 57, 1930–1937 (2020). https://doi.org/10.1007/s12035-019-01865-6

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