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Neuroprotective role of taurine during aging

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An Erratum to this article was published on 20 December 2013

Abstract

Aging of the brain is characterized by several neurochemical modifications involving structural proteins, neurotransmitters, neuropeptides and related receptors. Alterations of neurochemical indices of synaptic function are indicators of age-related impairment of central functions, such as locomotion, memory and sensory performances. Several studies demonstrate that ionotropic GABA receptors, glutamate decarboxylase (GAD), and somatostatinergic subpopulations of GABAergic neurons are markedly decreased in experimental animal brains during aging. Additionally, levels of several neuropeptides co-expressed with GAD decrease during aging. Thus, the age-related decline in cognitive functions could be attributable, at least in part, to decrements in GABA inhibitory neurotransmission. In this study, we showed that chronic supplementation of taurine to aged mice significantly ameliorated the age-dependent decline in spatial memory acquisition and retention. We also demonstrated that concomitant with the amelioration in cognitive function, taurine caused significant alterations in the GABAergic and somatostatinergic system. These changes included (1) increased levels of the neurotransmitters GABA and glutamate, (2) increased expression of both isoforms of GAD (65 and 67) and the neuropeptide somatostatin, (3) decreased hippocampal expression of the β3 subunits of the GABAA receptor, (4) increased expression in the number of somatostatin-positive neurons, (5) increased amplitude and duration of population spikes recorded from CA1 in response to Schaefer collateral stimulation and (6) enhanced paired pulse facilitation in the hippocampus. These specific alterations of the inhibitory system caused by taurine treatment oppose those naturally occurring in the aging brain, suggesting a protective role of taurine in this process. An increased understanding of age-related neurochemical changes in the GABAergic system will be important in elucidating the underpinnings of the functional changes of aging. Taurine supplementation might help forestall the age-related decline in cognitive functions through interaction with the GABAergic system.

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Abbreviations

GAD:

Glutamate decarboxylase

GABA:

γ-Aminobutyric acid

SST:

Somatostatin

DEPC:

Diethylpyrocarbonate

References

  • Araki T, Kato H, Fujiwara T, Itoyama Y (1996) Regional age-related alterations in cholinergic and GABAergic receptors in the rat brain. Mech Ageing Dev 88(1–2):49–60

    Article  CAS  PubMed  Google Scholar 

  • Banay-Schwartz M, Lajtha A, Palkovits M (1989a) Changes with aging in the levels of amino acids in rat CNS structural elements. I. Glutamate and related amino acids. Neurochem Res 14(6):555–562

    Article  CAS  PubMed  Google Scholar 

  • Banay-Schwartz M, Lajtha A, Palkovits M (1989b) Changes with aging in the levels of amino acids in rat CNS structural elements. II. Taurine and small neutral amino acids. Neurochem Res 14(6):563–570

    Article  CAS  PubMed  Google Scholar 

  • Bartfai T, Iverfeldt K, Fisone G, Serfozo P (1988) Regulation of the release of coexisting neurotransmitters. Annu Rev Pharmacol Toxicol 28:285–310. doi:10.1146/annurev.pa.28.040188.001441

    Article  CAS  PubMed  Google Scholar 

  • Benke D, Honer M, Michel C, Bettler B, Mohler H (1999) gamma-aminobutyric acid type B receptor splice variant proteins GBR1a and GBR1b are both associated with GBR2 in situ and display differential regional and subcellular distribution. J Biol Chem 274(38):27323–27330

    Article  CAS  PubMed  Google Scholar 

  • Bergmann I, Nitsch R, Frotscher M (1991) Area-specific morphological and neurochemical maturation of non-pyramidal neurons in the rat hippocampus as revealed by parvalbumin immunocytochemistry. Anat Embryol (Berl) 184(4):403–409

    Article  CAS  Google Scholar 

  • Bernard C, Wheal HV (1995) Expression of EPSP/spike potentiation following low frequency and tetanic stimulation in the CA1 area of the rat hippocampus. J Neurosci 15(10):6542–6551

    CAS  PubMed  Google Scholar 

  • Burianova J, Ouda L, Profant O, Syka J (2009) Age-related changes in GAD levels in the central auditory system of the rat. Exp Gerontol 44(3):161–169. doi:10.1016/j.exger.2008.09.012

    Article  CAS  PubMed  Google Scholar 

  • Caspary DM, Raza A, Lawhorn Armour BA, Pippin J, Arneric SP (1990) Immunocytochemical and neurochemical evidence for age-related loss of GABA in the inferior colliculus: implications for neural presbycusis. J Neurosci 10(7):2363–2372

    CAS  PubMed  Google Scholar 

  • Caspary DM, Milbrandt JC, Helfert RH (1995) Central auditory aging: GABA changes in the inferior colliculus. Exp Gerontol 30(3–4):349–360

    Article  CAS  PubMed  Google Scholar 

  • Caspary DM, Palombi PS, Hughes LF (2002) GABAergic inputs shape responses to amplitude modulated stimuli in the inferior colliculus. Hear Res 168(1–2):163–173

    Article  CAS  PubMed  Google Scholar 

  • Chattopadhyaya B, Di Cristo G, Wu CZ, Knott G, Kuhlman S, Fu Y, Palmiter RD, Huang ZJ (2007) GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron 54(6):889–903. doi:10.1016/j.neuron.2007.05.015

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cho YH, Friedman E, Silva AJ (1999) Ibotenate lesions of the hippocampus impair spatial learning but not contextual fear conditioning in mice. Behav Brain Res 98(1):77–87

    Article  CAS  PubMed  Google Scholar 

  • Curley AA, Eggan SM, Lazarus MS, Huang ZJ, Volk DW, Lewis DA (2013) Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: implications for schizophrenia. Neurobiol Dis 50:179–186. doi:10.1016/j.nbd.2012.10.018

    Article  CAS  PubMed  Google Scholar 

  • Decker MW, McGaugh JL (1989) Effects of concurrent manipulations of cholinergic and noradrenergic function on learning and retention in mice. Brain Res 477(1–2):29–37

    Article  CAS  PubMed  Google Scholar 

  • del Olmo N, Bustamante J, del Rio RM, Solis JM (2000) Taurine activates GABA(A) but not GABA(B) receptors in rat hippocampal CA1 area. Brain Res 864(2):298–307

    Article  PubMed  Google Scholar 

  • Denner LA, Wu JY (1985) Two forms of rat brain glutamic acid decarboxylase differ in their dependence on free pyridoxal phosphate. J Neurochem 44(3):957–965

    Article  CAS  PubMed  Google Scholar 

  • Deutch C, Spencer S, Robbins R, Cicchetti D, Spencer D (1991) Interictal spikes and hippocampal somatostatin levels in temporal lobe epilepsy. Epilepsia 32(2):174–178

    Article  CAS  PubMed  Google Scholar 

  • Dobkin C, Rabe A, Dumas R, El Idrissi A, Haubenstock H, Brown WT (2000) Fmr1 knockout mouse has a distinctive strain-specific learning impairment. Neuroscience 100(2):423–429

    Article  CAS  PubMed  Google Scholar 

  • Dumas RM, Rabe A (1994) Augmented memory loss in aging mice after one embryonic exposure to alcohol. Neurotoxicol Teratol 16(6):605–612

    Article  CAS  PubMed  Google Scholar 

  • El Idrissi A, L’Amoreaux WJ (2008) Selective resistance of taurine-fed mice to isoniazide-potentiated seizures: in vivo functional test for the activity of glutamic acid decarboxylase. Neuroscience 156(3):693–699. doi:10.1016/j.neuroscience.2008.07.055

    Article  PubMed  Google Scholar 

  • El Idrissi A, Trenkner E (1999) Growth factors and taurine protect against excitotoxicity by stabilizing calcium homeostasis and energy metabolism. J Neurosci 19(21):9459–9468

    PubMed  Google Scholar 

  • El Idrissi A, Trenkner E (2003) Taurine regulates mitochondrial calcium homeostasis. Adv Exp Med Biol 526:527–536

    Article  PubMed  Google Scholar 

  • El Idrissi A, Trenkner E (2004) Taurine as a modulator of excitatory and inhibitory neurotransmission. Neurochem Res 29(1):189–197

    Article  PubMed  Google Scholar 

  • El Idrissi A, Messing J, Scalia J, Trenkner E (2003) Prevention of epileptic seizures by taurine. Adv Exp Med Biol 526:515–525

    Article  PubMed  Google Scholar 

  • El Idrissi A, Ding XH, Scalia J, Trenkner E, Brown WT, Dobkin C (2005) Decreased GABA(A) receptor expression in the seizure-prone fragile X mouse. Neurosci Lett 377(3):141–146. doi:10.1016/j.neulet.2004.11.087

    Article  PubMed  Google Scholar 

  • El Idrissi A, Neuwirth L, L’Amoreaux W (2010) Taurine regulation of short term synaptic plasticity in fragile X mice. J Biomed Sci 17:S15. doi:10.1186/1423-0127-17-S1-S15

    Article  PubMed  Google Scholar 

  • Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ (1991) Two genes encode distinct glutamate decarboxylases. Neuron 7(1):91–100

    Article  CAS  PubMed  Google Scholar 

  • Esclapez M, Tillakaratne NJ, Kaufman DL, Tobin AJ, Houser CR (1994) Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci 14(3 Pt 2):1834–1855

    CAS  PubMed  Google Scholar 

  • Ford J, Odeyale O, Eskandar A, Kouba N, Shen CH (2007) A SWI/SNF- and INO80-dependent nucleosome movement at the INO1 promoter. Biochem Biophys Res Commun 361(4):974–979. doi:10.1016/j.bbrc.2007.07.109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Govoni S, Memo M, Saiani L, Spano PF, Trabucchi M (1980) Impairment of brain neurotransmitter receptors in aged rats. Mech Ageing Dev 12(1):39–46

    Article  CAS  PubMed  Google Scholar 

  • Gutierrez A, Khan ZU, Morris SJ, De Blas AL (1994) Age-related decrease of GABAA receptor subunits and glutamic acid decarboxylase in the rat inferior colliculus. J Neurosci 14(12):7469–7477

    CAS  PubMed  Google Scholar 

  • Hokfelt T (1991) Neuropeptides in perspective: the last ten years. Neuron 7(6):867–879

    Article  CAS  PubMed  Google Scholar 

  • Hong A, Zhang A, Ke Y, El Idrissi A, Shen C-H (2012) Downregulation of GABAA β Subunits is Transcriptionally Controlled by Fmr1p. J Mol Neurosci 46(2):272–275. doi:10.1007/s12031-011-9531-5

    Article  CAS  PubMed  Google Scholar 

  • Hunter C, Chung E, Van Woert MH (1989) Age-dependent changes in brain glycine concentration and strychnine-induced seizures in the rat. Brain Res 482(2):247–251

    Article  CAS  PubMed  Google Scholar 

  • Huxtable RJ (1989) Taurine in the central nervous system and the mammalian actions of taurine. Prog Neurobiol 32(6):471–533

    Article  CAS  PubMed  Google Scholar 

  • Huxtable RJ (1992) Physiological actions of taurine. Physiol Rev 72(1):101–163

    CAS  PubMed  Google Scholar 

  • Ishibashi H, Akaike N (1995) Somatostatin modulates high-voltage-activated Ca2 + channels in freshly dissociated rat hippocampal neurons. J Neurophysiol 74(3):1028–1036

    CAS  PubMed  Google Scholar 

  • Jiang M, Swann JW (1997) Expression of calretinin in diverse neuronal populations during development of rat hippocampus. Neuroscience 81(4):1137–1154

    Article  CAS  PubMed  Google Scholar 

  • Kash SF, Tecott LH, Hodge C, Baekkeskov S (1999) Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 96(4):1698–1703

    Article  CAS  PubMed  Google Scholar 

  • Kuriyama K, Hashimoto T (1998) Interrelationship between taurine and GABA. Adv Exp Med Biol 442:329–337

    Article  CAS  PubMed  Google Scholar 

  • Kuwahara S, Kesuma Sari D, Tsukamoto Y, Tanaka S, Sasaki F (2004a) Age-related changes in growth hormone (GH)-releasing hormone and somatostatin neurons in the hypothalamus and in GH cells in the anterior pituitary of female mice. Brain Res 1025(1–2):113–122. doi:10.1016/j.brainres.2004.08.012

    Article  CAS  PubMed  Google Scholar 

  • Kuwahara S, Sari DK, Tsukamoto Y, Tanaka S, Sasaki F (2004b) Age-related changes in growth hormone (GH) cells in the pituitary gland of male mice are mediated by GH-releasing hormone but not by somatostatin in the hypothalamus. Brain Res 998(2):164–173

    Article  CAS  PubMed  Google Scholar 

  • Laming PR, Elwood RW, Best PM (1989) Epileptic tendencies in relation to behavioral responses to a novel environment in the Mongolian gerbil. Behav Neural Biol 51(1):92–101

    Article  CAS  PubMed  Google Scholar 

  • Lehmann K, Steinecke A, Bolz J (2012) GABA through the ages: regulation of cortical function and plasticity by inhibitory interneurons. Neural Plast 2012:892784. doi:10.1155/2012/892784

    PubMed Central  PubMed  Google Scholar 

  • Ling LL, Hughes LF, Caspary DM (2005) Age-related loss of the GABA synthetic enzyme glutamic acid decarboxylase in rat primary auditory cortex. Neuroscience 132(4):1103–1113. doi:10.1016/j.neuroscience.2004.12.043

    Article  CAS  PubMed  Google Scholar 

  • Logue SF, Paylor R, Wehner JM (1997) Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task. Behav Neurosci 111(1):104–113

    Article  CAS  PubMed  Google Scholar 

  • Manfridi A, Forloni GL, Vezzani A, Fodritto F, De Simoni MG (1991) Functional and histological consequences of quinolinic and kainic acid-induced seizures on hippocampal somatostatin neurons. Neuroscience 41(1):127–135

    Article  CAS  PubMed  Google Scholar 

  • Marczynski TJ (1998) GABAergic deafferentation hypothesis of brain aging and Alzheimer’s disease revisited. Brain Res Bull 45(4):341–379

    Article  CAS  PubMed  Google Scholar 

  • Mellor JR, Gunthorpe MJ, Randall AD (2000) The taurine uptake inhibitor guanidinoethyl sulphonate is an agonist at gamma-aminobutyric acid(A) receptors in cultured murine cerebellar granule cells. Neurosci Lett 286(1):25–28

    Article  CAS  PubMed  Google Scholar 

  • Mendelson JR, Ricketts C (2001) Age-related temporal processing speed deterioration in auditory cortex. Hear Res 158(1–2):84–94

    Article  CAS  PubMed  Google Scholar 

  • Milbrandt JC, Albin RL, Turgeon SM, Caspary DM (1996) GABAA receptor binding in the aging rat inferior colliculus. Neuroscience 73(2):449–458

    Article  CAS  PubMed  Google Scholar 

  • Monno A, Rizzi M, Samanin R, Vezzani A (1993) Anti-somatostatin antibody enhances the rate of hippocampal kindling in rats. Brain Res 602(1):148–152

    Article  CAS  PubMed  Google Scholar 

  • Moore SD, Madamba SG, Joels M, Siggins GR (1988) Somatostatin augments the M-current in hippocampal neurons. Science 239(4837):278–280

    Article  CAS  PubMed  Google Scholar 

  • Naus CC, Miller FD, Morrison JH, Bloom FE (1988) Immunohistochemical and in situ hybridization analysis of the development of the rat somatostatin-containing neocortical neuronal system. J Comp Neurol 269(3):448–463. doi:10.1002/cne.902690311

    Article  CAS  PubMed  Google Scholar 

  • Nishimura T, Schwarzer C, Furtinger S, Imai H, Kato N, Sperk G (2001) Changes in the GABA-ergic system induced by trimethyltin application in the rat. Brain Res Mol Brain Res 97(1):1–6

    Article  CAS  PubMed  Google Scholar 

  • Oliva AA Jr, Jiang M, Lam T, Smith KL, Swann JW (2000) Novel hippocampal interneuronal subtypes identified using transgenic mice that express green fluorescent protein in GABAergic interneurons. J Neurosci 20(9):3354–3368

    CAS  PubMed  Google Scholar 

  • Paul LA, Fried I, Watanabe K, Forsythe AB, Scheibel AB (1981) Structural correlates of seizure behavior in the mongolian gerbil. Science 213(4510):924–926

    Article  CAS  PubMed  Google Scholar 

  • Perez J, Vezzani A, Civenni G, Tutka P, Rizzi M, Schupbach E, Hoyer D (1995) Functional effects of D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2 and differential changes in somatostatin receptor messenger RNAs, binding sites and somatostatin release in kainic acid-treated rats. Neuroscience 65(4):1087–1097

    Article  CAS  PubMed  Google Scholar 

  • Pitari G, Malergue F, Martin F, Philippe JM, Massucci MT, Chabret C, Maras B, Dupre S, Naquet P, Galland F (2000) Pantetheinase activity of membrane-bound Vanin-1: lack of free cysteamine in tissues of Vanin-1 deficient mice. FEBS Lett 483(2–3):149–154

    Article  PubMed  Google Scholar 

  • Quinn MR, Harris CL (1995) Taurine allosterically inhibits binding of [35S]-t-butylbicyclophosphorothionate (TBPS) to rat brain synaptic membranes. Neuropharmacology 34(12):1607–1613

    Article  CAS  PubMed  Google Scholar 

  • Ramirez M, Gutierrez R (2001) Activity-dependent expression of GAD67 in the granule cells of the rat hippocampus. Brain Res 917(2):139–146

    Article  CAS  PubMed  Google Scholar 

  • Raza A, Milbrandt JC, Arneric SP, Caspary DM (1994) Age-related changes in brainstem auditory neurotransmitters: measures of GABA and acetylcholine function. Hear Res 77(1–2):221–230

    Article  CAS  PubMed  Google Scholar 

  • Ribak CE, Lauterborn JC, Navetta MS, Gall CM (1993) The inferior colliculus of GEPRs contains greater numbers of cells that express glutamate decarboxylase (GAD67) mRNA. Epilepsy Res 14(2):105–113

    Article  CAS  PubMed  Google Scholar 

  • Schwarzer C, Williamson JM, Lothman EW, Vezzani A, Sperk G (1995) Somatostatin, neuropeptide Y, neurokinin B and cholecystokinin immunoreactivity in two chronic models of temporal lobe epilepsy. Neuroscience 69(3):831–845

    Article  CAS  PubMed  Google Scholar 

  • Spink DC, Wu SJ, Martin DL (1983) Multiple forms of glutamate decarboxylase in porcine brain. J Neurochem 40(4):1113–1119

    Article  CAS  PubMed  Google Scholar 

  • Sturman JA (1993) Taurine in development. Physiol Rev 73(1):119–147

    CAS  PubMed  Google Scholar 

  • Sun QQ, Huguenard JR, Prince DA (2002) Somatostatin inhibits thalamic network oscillations in vitro: actions on the GABAergic neurons of the reticular nucleus. J Neurosci 22(13):5374–5386

    CAS  PubMed  Google Scholar 

  • Vezzani A, Hoyer D (1999) Brain somatostatin: a candidate inhibitory role in seizures and epileptogenesis. Eur J Neurosci 11(11):3767–3776. doi:10.1046/j.1460-9568.1999.00838.x

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Ruiz R, Monno A, Rizzi M, Lindefors N, Samanin R, Brodin E (1993) Extracellular somatostatin measured by microdialysis in the hippocampus of freely moving rats: evidence for neuronal release. J Neurochem 60(2):671–677

    Article  CAS  PubMed  Google Scholar 

  • Wang DS, Xu TL, Pang ZP, Li JS, Akaike N (1998) Taurine-activated chloride currents in the rat sacral dorsal commissural neurons. Brain Res 792(1):41–47

    Article  CAS  PubMed  Google Scholar 

  • Wimalarathna R, Tsai CH, Shen CH (2011) Transcriptional control of genes involved in yeast phospholipid biosynthesis. J Microbiol 49(2):265–273. doi:10.1007/s12275-011-1130-1

    Article  CAS  PubMed  Google Scholar 

  • Wu JY, Tang XW, Schloss JV, Faiman MD (1998) Regulation of taurine biosynthesis and its physiological significance in the brain. Adv Exp Med Biol 442:339–345

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Liang Z, Li G, Wang Y, Zhou Y, Leventhal AG (2008) Aging affects contrast response functions and adaptation of middle temporal visual area neurons in rhesus monkeys. Neuroscience 156(3):748–757. doi:10.1016/j.neuroscience.2008.08.007

    Article  CAS  PubMed  Google Scholar 

  • Zhang A, Shen CH, Ma SY, Ke Y, El Idrissi A (2009) Altered expression of Autism-associated genes in the brain of Fragile X mouse model. Biochem Biophys Res Commun 379(4):920–923. doi:10.1016/j.bbrc.2008.12.172

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z, Cai YQ, Zou F, Bie B, Pan ZZ (2011) Epigenetic suppression of GAD65 expression mediates persistent pain. Nat Med 17(11):1448–1455. doi:10.1038/nm.2442

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Support for this work was provided by the College of Staten Island/CUNY, PSC-CUNY, and CDN-IBR and FRAXA. Support for the confocal microscope came from the National Science Foundation.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biology, Center for Developmental Neuroscience, City University of New York Graduate School, Staten Island, NY, 10314, USA

    Abdeslem El Idrissi, Chang Hui Shen & William J. L’Amoreaux

  2. The Graduate Center, Program in Biology-Neurosciences, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA

    Abdeslem El Idrissi & William J. L’Amoreaux

  3. The Graduate Center, Program in Biology-Molecular, Cellular and Developmental Biology, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA

    Chang Hui Shen

  4. The Graduate Center, Program in Biochemistry, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA

    William J. L’Amoreaux

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El Idrissi, A., Shen, C.H. & L’Amoreaux, W.J. Neuroprotective role of taurine during aging. Amino Acids 45, 735–750 (2013). https://doi.org/10.1007/s00726-013-1544-7

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