Distinct behavioral effects of short-term voluntary running in phosphatase and tensin homolog deleted on chromosome 10 neuronal haploinsufficient mice
Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a tumor suppressor with functions related to its phosphatase activity. PTEN plays various roles, such as cell proliferation, survival, and migration and is involved in neurogenesis and synaptic plasticity in the central nervous system. It has been reported that running could have protective effects against the aging process and neurodegenerative diseases. Therefore, we aimed to evaluate the effects of physical exercise on behavioral and biochemical aspects of PTEN-conditioned knockout female mice. We observed that 10 days of voluntary running positively affected fear memory but caused no changes in anxiety-like behavior. However, it was unable to counteract the social recognition memory deficit in PTEN neuronal haploinsufficient mice. In terms of biochemical aspects, we observed that short-term running reduced S6 phosphorylation in PTEN heterozygous mice and PTEN protein expression independent of the genotype. In addition, PTEN heterozygous mice presented reduced N-methyl-D-aspartate subunit NR1 protein expression. Our results regarding decreased S6 phosphorylation in HT mice suggest that short-term voluntary running could have induced a protective effect in reducing dysregulated cell growth, possibly related to the downregulation of tumor suppressor expression/activity such as PTEN. Moreover, running induced distinct behavioral effects in PTEN-conditioned knockout mice.
- Steck PA, Pershouse MA, Jasser S, et al., 1997, Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet, 15: 356–362. https://doi.org/10.1038/ng0497-356
- Li J, Yen C, Liaw D, et al., 1997, PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science, 275: 1943–1947. https://doi.org/10.1126/science.275.5308.1943
- Maehama T, Dixon JE, 1998, The tumor suppressor PTEN/ MMAC1, dephosphorylates the lipid second messenger phosphadylinositol 3,4,5-triphosphate. J Biol Chem, 273: 13375–13378. https://doi.org/10.1074/jbc.273.22.13375
- Ruvinsky I, Sharon N, Lere T, et al., 2005, Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev, 19: 2199–2211. https://doi.org/10.1101/gad.351605
- Ruvinsky I, Meyuhas O, 2006, Ribosomal protein S6 phosphorylation: From protein synthesis to cell size. Trends Biochem Sci, 31: 342–348. https://doi.org/10.1016/j.tibs.2006.04.003
- Perandones C, Costanzo RV, Kowaljow V, et al., 2004, Correlation between synaptogenesis and the PTEN phosphatase expression in dendrites during postnatal brain development. Brain Res Mol Brain Res, 128: 8–19. https://doi.org/10.1016/j.molbrainres.2004.05.021
- Backman SA, Stambolic V, Suzuki A, et al., 2001, Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet, 29: 396–403. https://doi.org/10.1038/ng782
- Groszer M, Erickson R, Scripture-Adams DD, et al., 2001, Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science, 294: 2186–2189. https://doi.org/10.1126/science.1065518
- Kwon CH, Zhu X, Zhang J, et al., 2001, Pten regulates neuronal soma size: A mouse model of Lhermitte-Duclos disease. Nat Genet, 29: 404–411. https://doi.org/10.1038/ng781
- Marin S, Krimpenfort P, Leung C, et al., 2002, PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum. Development, 129: 3513–3522. https://doi.org/10.1242/dev.129.14.3513
- Kwon CH, Zhu X, Zhang J, et al., 2003, mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc Natl Acad Sci U S A, 100: 12923–12928. https://doi.org/10.1073/pnas.2132711100
- Liaw D, Marsch DJ, Li J, et al., 1997, Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet, 16: 64–67. https://doi.org/10.1038/ng0597-64
- Marsh DJ, Coulon V, Luneeta KL, et al., 1998, Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet, 7: 507–515. https://doi.org/10.1093/hmg/7.3.507
- Di Cristofano A, Pesce B, Cordon-Cardo C, et al., 1998, Pten is essential for embryonic development and tumor suppression. Nat Genet, 19: 348–355. https://doi.org/10.1038/1235
- Podsypanina K, Ellenson LH, Nemes A, et al., 1999, Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ system. Proc Natl Acad Sci U S A, 96: 1563–1568. https://doi.org/10.1073/pnas.96.4.1563
- Stambolic V, Suzuki A, de la Pompa JL, et al., 1998, Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 95: 29–39. https://doi.org/10.1016/s0092-8674(00)81780-8
- Suzuki A, de La Pomap JL, Stambolic V, et al., 1998, High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol, 8: 1169–1178. https://doi.org/10.1016/s0960-9822(07)00488-5
- Butler MG, Dasouki MJ, Zhou XP, et al., 2005, Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet, 42: 318–321. https://doi.org/10.1136/jmg.2004.024646
- Kwon CH, Luikart BW, Powell CM, et al., 2006, Pten regulates neuronal arborization and social interaction in mice. Neuron, 50: 377–388. https://doi.org/10.1016/j.neuron.2006.03.023
- Shin S, Santi A, Huang S, 2021, Conditional Pten knockout in parvalbumin- or somatostatin-positive neurons sufficiently leads to autism-related behavioral phenotypes. Mol Brain, 14: 24. https://doi.org/10.1186/s13041-021-00731-8
- Cupolillo D, Hoxha E, Faralli A, et al., 2016, Autistic-like traits and cerebellar dysfunction in Purkinje cell PTEN Knock-out mice. Neuropsychopharmacology, 41: 1457–1466. https://doi.org/10.1038/npp.2015.339
- Zhu S, Stein RA, Yoshioka C, et al., 2016, Mechanism of NMDA receptor inhibition and activation. Cell, 165: 704–714. https://doi.org/10.1016/j.cell.2016.03.028
- Jurado S, Benoist M, Lario A, et al., 2010, PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression. EMBO J, 29: 2827–2840. https://doi.org/10.1038/emboj.2010.160
- Gligoroska JP, Manchevska S, 2012, The effect of physical activity on cognition – Physiological mechanisms. Mater Sociomed, 24: 198-202. https://doi.org/ 10.5455/msm.2012.24.198-202
- Creer DJ, Romberg C, Saksida LM, et al., 2010, Running enhances spatial pattern separation in mice. Proc Natl Acad Sci U S A, 107: 2367–2372. https://doi.org/10.1073/pnas.0911725107
- Kempermann G, Fabel K, Ehninger D, et al., 2010, Why and how physical activity promotes experience-induced brain plasticity. Front Neurosci, 4: 189. https://doi.org/10.3389/fnins.2010.00189
- van Praag H, 2008, Neurogenesis and exercise: Past and future directions. Neuromolecular Med, 10: 128–140. https://doi.org/10.1007/s12017-008-8028-z
- Seifert T, Brassard P, Wissenberg M, et al., 2010, Endurance training enhances BDNF release from the human brain. Am J Physiol Regul Integr Comp Physiol, 298: R372–R377. https://doi.org/10.1152/ajpregu.00525.2009
- Mattson MP, 2012, Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab, 16: 706–722. https://doi.org/10.1016/j.cmet.2012.08.012
- Dietrich MO, Mantese CE, Porciuncula LO, et al., 2005, Exercise affects glutamate receptors in postsynaptic densities from cortical mice brain. Brain Res, 1065: 20–25. https://doi.org/10.1016/j.brainres.2005.09.038
- van Praag H, Kempermann G, Gage FH, 1999, Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci, 2: 266–270. https://doi.org/10.1038/6368
- Allen DM, van Praag H, Ray J, et al., 2001, Ataxia telangiectasia mutated is essential during adult neurogenesis. Genes Dev, 15: 554–566. https://doi.org/10.1101/gad.869001
- Persson AI, Naylor AS, Jonsdottir IH, et al., 2004, Differential regulation of hippocampal progenitor proliferation by opioid receptor antagonists in running and non‐running spontaneously hypertensive rats. Eur J Neurosci, 19: 1847–1855. https://doi.org/10.1111/j.1460-9568.2004.03268.x
- Lattanzi D, Savelli D, Pagliarini M, et al., 2022, Short-term, voluntary exercise affects morpho-functional maturation of adult-generated neurons in rat hippocampus. Int J Mol Sci, 23: 6866. https://doi.org/10.3390/ijms23126866
- Kawamoto EM, Scavone C, Mattson MP, et al., 2013, Curcumin requires tumor necrosis factor α signaling to alleviate cognitive impairment elicited by lipopolyssacharide. Neurosignals, 21: 75–88. https://doi.org/10.1159/000336074
- Texel SJ, Camandola S, Ladenheim B, et al., 2012, Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF. J Neurochem, 120: 125–134. https://doi.org/10.1111/j.1471-4159.2011.07554.x
- Moy SS, Nadler JJ, Perez A, et al., 2004, Sociability and preference for social novelty in five inbread strains: An approach to acess autist-like behavior in mice. Genes Brain Behav, 3: 287–302. https://doi.org/10.1111/j.1601-1848.2004.00076.x
- Nadler JJ, Moy SS, Dold G, et al., 2004, Automated apparatus for quantification of social approach behaviors in mice. Genes Brain Behav, 3: 303–314. https://doi.org/10.1111/j.1601-183X.2004.00071.x
- Cabral-Costa JV, Andreotti DZ, Mell NP, et al., 2018, Intermittent fasting uncovers and rescues cognitive phenotypes in PTEN neuronal haploinsufficient mice. Sci Rep, 8: 8595. https://doi.org/10.1038/s41598-018-26814-6
- Vasconcelos AR, Yshii LM, Viel TA, et al., 2014, Intermittent fasting attennuates lipopolysaccharide - induced neuroinflammation and memory impairment. J Neuroinflamation, 11: 85. https://doi.org/10.1186/1742-2094-11-85
- Bradford MM, 1976, A rapid and sensitive methods for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem, 72: 248–254. https://doi.org/10.1006/abio.1976.9999
- Laemmli UK, 1970, Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227: 680–685. https://doi.org/10.1038/227680a0
- Chiang MC, Huang AJY, Wintzer ME, et al., 2018, A role for CA3 in social recognition memory. Behav Brain Res, 354: 22–30. https://doi.org/10.1016/j.bbr.2018.01.019
- Vasconcelos AR, da Paixão AG, Kinoshita PF, et al., 2021, Toll-like receptor 4 signaling is critical for the adaptive cellular stress response effects induced by intermittent fasting in the mouse brain. Neuroscience, 465: 142–153. https://doi.org/10.1016/j.neuroscience.2021.04.022
- Rhodes JS, Garland T, Gammie SC, 2003, Patterns of brain activity associated with variation in voluntary wheel-running behavior. Behav Neurosci, 117: 1243–1256. https://doi.org/10.1037/0735-7044.117.6.1243
- Konhilas JP, Maass AH, Luckey SW, et al., 2004, Sex modifies exercise and cardiac adaptation in mice. Am J Physiol Heart Circ Physiol, 287: H2768–H2776. https://doi.org/10.1152/ajpheart.00292.2004
- De Bono JP, Adlam D, Paterson DJ, et al., 2006, Novel quantitative phenotypes of exercise training in mouse models. Am J Physiol Regul Integr Comp Physiol, 290: R926–R934. https://doi.org/10.1152/ajpregu.00694.2005
- Liu Y, Yan T, Chu JM, et al., 2019, The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases. Lab Invest, 99: 943–957. https://doi.org/10.1038/s41374-019-0232-y
- Barnes JN, 2015, Exercise, cognitive function and aging. Adv Physiol Educ, 39: 55–62. https://doi.org/10.1152/advan.00101.2014
- Tabei KL, Satoh M, Ogawa JI, et al., 2018, Cognitive function and brain atrophy predict non-pharmacological efficacy in dementia: The mihama-kiho scan project 2. Front Aging Neurosci, 10: 87. https://doi.org/10.3389/fnagi.2018.00087
- Sefen JAN, Al-Salmi S, Shaikh Z, et al., 2020, Beneficial use and potential effectiveness of physical activity in managing autism spectrum disorder. Front Behav Neurosci, 14: 587560. https://doi.org/10.3389/fnbeh.2020.587560
- Otsuka A, Shiuchi T, Chikahisa S, et al., 2015, Voluntary exercise and increased food intake after mild chronic stress improve social avoidance behavior in mice. Physiol Behav, 151: 264–271. https://doi.org/10.1016/j.physbeh.2015.07.024
- Manzanares G, Brito-da-Silva G, Gandra PG, 2018, Voluntary wheel running: Patterns and physiological effects in mice. Braz J Med Biol Res, 52: e7830. https://doi.org/10.1590/1414-431X20187830
- Clipperton-Allen AE, Page DT, 2014, Ptenhaploinsufficient mice show broad brain overgrowth but selective impairments in autism-relevant behavioral tests. Hum Mol Genet, 23: 3490–3505. https://doi.org/10.1093/hmg/ddu057
- Ogawa S, Kwon CH, Zhou J, et al., 2007, A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice. Brain Res, 1168: 112–123. https://doi.org/10.1016/j.brainres.2007.06.074
- Lugo JN, Smith GD, Arbuckle EP, et al., 2014, Deletion of PTEN produces autism like behavioral deficits and alterations in synaptic proteins. Front Mol Neurosci, 7: 27. https://doi.org/10.3389/fnmol.2014.00027
- Pierce K, Conant D, Hazin R, et al., 2011, Preference for geometric patterns early in life as a risk factor for autism. Arch Gen Psychiatry, 68: 101–109. https://doi.org/10.1001/archgenpsychiatry.2010.113
- Zhou J, Parada LF, 2012, PTEN signaling in autism spectrum disorders. Curr Opin Neurobiol, 22: 873–879. https://doi.org/10.1016/j.conb.2012.05.004
- Hill EL, Frith U, 2003, Understanding autism: Insights from mind and brain. Philos Trans R Soc Lond B Biol Sci, 358: 281–289. https://doi.org/10.1098/rstb.2002.1209
- Zhang Y, Niu L, Zhang D, et al., 2019, Social-emotional functioning explains the effects of physical activity on academic performance among Chinese primary school students: A mediation analysis. J Pediatr, 208: 74–80. https://doi.org/10.1016/j.jpeds.2018.11.045
- Van Praag H, 2005, Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci, 25: 8680–8685. https://doi.org/10.1523/JNEUROSCI.1731-05.2005
- Moon HY, Becke A, Berron D, et al., 2016, Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab, 24: 332–340. https://doi.org/10.1016/j.cmet.2016.05.025
- Loomes R, Hull L, Mandy WPL, 2017, What is the male-to-female ration in autism spectrum disorder? A systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry, 56: 466–474. https://doi.org/10.1016/j.jaac.2017.03.013
- Kim YS, Leventhal BL, Koh YJ, et al., 2011, Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry, 168: 904–912. https://doi.org/10.1176/appi.ajp.2011.10101532
- Liu G, Feng D, Wang J, et al., 2018, rTMS ameliorates PTSD symptoms in rats by enhancing glutamate transmission and synaptic plasticity in the ACC via the PTEN/AKT signaling pathway. Mol Neurobiol, 55: 3946–3958. https://doi.org/10.1007/s12035-017-0602-7
- Rubenstein JLR, 2010, Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder. Curr Opin Neurol, 23: 118–123. https://doi.org/10.1097/WCO.0b013e328336eb13
- Marchese M, Conti V, Valvo G, et al., 2014, Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM genetic screening. BMC Med Genet, 15: 26.
- Christensen J, Gronborg TK, Sorensen MJ, et al., 2013, Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA, 309: 1696–1703. https://doi.org/10.1001/jama.2013.2270
- Bescoby-Chambers N, Forster P, Bates G, et al., 2001, Foetal valproate syndrome and autism: Additional evidence of an association. Dev Med Child Neurol, 43: 847. https://doi.org/10.1017/s0012162201211542
- Rinaldi T, Kulangara K, Antoniello K, et al., 2007, Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A, 104: 13501–13506. https://doi.org/10.1073/pnas.0704391104
- Wang X, Kery R, Xiong Q, et al., 2018, Synaptopathology in autism spectrum disorders: Complex effects of synaptic genes on neural circuits. Prog Neuropsychopharmacol Biol Psychiatry, 84: 398–415. https://doi.org/10.1016/j.pnpbp.2017.09.026
- Fenton TR, Gout IT, 2011, Functions and regulation of the 70kDa ribosomal S6 kinase. Int J Biochem Cell Biol, 43: 47–59. https://doi.org/10.1016/j.biocel.2010.09.018
- Baar K, Esser K, 1999, Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am J Physiol, 276: C120–C127. https://doi.org/10.1152/ajpcell.1999.276.1.C120
- Terzis G, Spengos K, Mascher H, et al., 2010, The degree of p70S6k and S6 phosphorylation in human skeletal muscle in response to resistance exercise depends on the training volume. Eur J Appl Physiol, 110: 835–843. https://doi.org/10.1007/s00421-010-1527-2
- Caccamo A, Branca C, Talboom JS, et al., 2015, Reducing ribosomal protein S6 kinase 1 expression improves spatial memory and synaptic plasticity in a mouse model of Alzheimer’s disease. J Neurosci, 35: 14042–14056. https://doi.org/10.1523/JNEUROSCI.2781-15.2015
- Rothman SM, Olney JW, 1986, Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol, 19: 105–111. https://doi.org/10.1002/ana.410190202
- Lenz G, Avruch J, 2005, Glutamatergic regulation of the p70S6kinase in primary mouse neurons. J Biol Chem, 280: 38121–38124. https://doi.org/10.1074/jbc.C500363200
- Weston MC, Chen H, Swann JW, 2012, Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci, 32: 11441–11452. https://doi.org/10.1523/JNEUROSCI.1283-12.2012
- Williams MR, DeSpenza T Jr., Li M, et al., 2015, Hyperactivity of newborn PTEN knock-out neurons results from increased excitatory synaptic drive. J Neurosci, 35: 943–959. https://doi.org/10.1523/JNEUROSCI.3144-14.2015
- Antion MD, Merhav M, Hoeffer CA, et al., 2008, Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity. Learn Mem, 15: 29–38. https://doi.org/10.1101/lm.661908
- Cammalleri M, Lutjens R, Berton F, et al., 2003, Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. Proc Natl Acad Sci U S A, 100: 14368–14373. https://doi.org/10.1073/pnas.2336098100
- Raymond CR, Redman SJ, Crouch MF, 2002, The phosphoinositide 3-kinase and p70 S6 kinase regulate long-term potentiation in hippocampal neurons. Neuroscience, 109: 531–536. https://doi.org/10.1016/s0306-4522(01)00500-0
- Paez JG, Sellers WR, 2003, PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res, 115: 145–167.
- Yu M, King B, Ewert E, et al., 2016, Exercise activates p53 and negatively regulates IGF-1 pathway in epidermis within a skin cancer model. PLoS One, 11: e0160939. https://doi.org/10.1371/journal.pone.0160939
- Gonzalez MD, Buberman A, Morales M, et al., 2021, Aberrant synaptic PTEN in symptomatic Alzheimer’s patients may link synaptic depression to network failure. Front Synaptic Neurosci, 13: 683290. https://doi.org/10.3389/fnsyn.2021.683290
- Rosenfeld CS, 2017, Sex-dependent differences in voluntary physical activity. J Neurosci Res, 95: 279–290. https://doi.org/10.1002/jnr.23896
- de Mello NP, Andreotti DZ, Orellana AM, et al., 2020, Inverse sex-based expression profiles of PTEN and Klotho in mice. Sci Rep, 10: 20189. https://doi.org/10.1038/s41598-020-77217-5
- Auyeung B, Taylor K, Hackett G, et al., 2010, Foetal testosterone and autistic traits in 18 to 24-month-old children. Mole Autism, 1: 11. https://doi.org/10.1186/2040-2392-1-11