Abstract
The main glutamate transporter GLT-1 is responsible for clearing synaptically released glutamate from the extracellular space and contributes to the shaping of glutamatergic transmission. Recently, it has been shown that ceftriaxone (CEF)-induced GLT-1 upregulation is associated with an impairment of the prepulse inhibition (PPI) of the startle reflex, a simple form of information processing that is reduced in schizophrenia, and determines a strong reduction in hippocampal metabotropic glutamate receptor (mGluR)2/3-dependent long-term depression. In this study, we tested the hypothesis that administration of the mGluR2/3 agonist LY379268 blocks the effect of GLT-1 upregulation on PPI of the startle. We showed that administration of LY379268 (1 mg/kg) prevented PPI alterations associated with GLT-1 upregulation, suggesting that CEF-induced PPI impairment was mGluR2/3 dependent. In addition, we showed that CEF-induced GLT-1 upregulaton did not alter the expression of mGluR2/3, and also that it occurred at sites of mGluR2/3 expression. These results indicate a novel mechanism by which GLT-1 upregulation modulates PPI of the startle.
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References
Andreasen NC (1997). Linking mind and brain in the study of mental illnesses: a project for a scientific psychopathology. Science 275: 1586–1593.
Andreasen NC (2000). Schizophrenia: the fundamental questions. Brain Res Brain Res Rev 31: 106–112.
Barbour B (2001). An evaluation of synapse independence. J Neurosci 21: 7969–7984.
Barr AM, Lehmann-Masten V, Paulus M, Gainetdinov RR, Caron MG, Geyer MA (2004). The selective serotonin-2A receptor antagonist M100907 reverses behavioral deficits in dopamine transporter knockout mice. Neuropsychopharmacology 29: 221–228.
Beart PM, O'Shea RD (2007). Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol 150: 5–17.
Bellesi M, Melone M, Gubbini A, Battistacci S, Conti F (2009). GLT-1 upregulation impairs prepulse inhibition of the startle reflex in adult rats. Glia 57: 703–713.
Braff DL, Geyer MA (1990). Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47: 181–188.
Braff DL, Geyer MA, Swerdlow NR (2001). Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156: 234–258.
Braff DL, Grillon C, Geyer MA (1992). Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49: 206–215.
Braff DL, Light GA, Swerdlow NR (2007). Prepulse inhibition and P50 suppression are both deficient but not correlated in schizophrenia patients. Biol Psychiatry 61: 1204–1207.
Bragina L, Melone M, Fattorini G, Torres-Ramos M, Vallejo-Illarramendi A, Matute C et al (2006). GLT-1 down-regulation induced by clozapine in rat frontal cortex is associated with synaptophysin up-regulation. J Neurochem 99: 134–141.
Cartmell J, Monn JA, Schoepp DD (1999). The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 291: 161–170.
Cartmell J, Monn JA, Schoepp DD (2000). Attenuation of specific PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine. Psychopharmacology (Berl) 148: 423–429.
Chen W, Mahadomrongkul V, Berger UV, Bassan M, DeSilva T, Tanaka K et al (2004). The glutamate transporter GLT1a is expressed in excitatory axon terminals of mature hippocampal neurons. J Neurosci 24: 1136–1148.
Chu K, Lee ST, Sinn DI, Ko SY, Kim EH, Kim JM et al (2007). Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation. Stroke 38: 177–182.
Clark M, Johnson BG, Wright RA, Monn JA, Schoepp DD (2002). Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats. Pharmacol Biochem Behav 73: 339–346.
Conti F, Weinberg RJ (1999). Shaping excitation at glutamatergic synapses. Trends Neurosci 22: 451–458.
Danbolt NC (2001). Glutamate uptake. Prog Neurobiol 65: 1–105.
Danbolt NC, Pines G, Kanner BI (1990). Purification and reconstitution of the sodium- and potassium-coupled glutamate transport glycoprotein from rat brain. Biochemistry 29: 6734–6740.
Dawson ME, Schell AM, Hazlett EA, Nuechterlein KH, Filion DL (2000). On the clinical and cognitive meaning of impaired sensorimotor gating in schizophrenia. Psychiatry Res 96: 187–197.
Deng X, Shibata H, Ninomiya H, Tashiro N, Iwata N, Ozaki N et al (2004). Association study of polymorphisms in the excitatory amino acid transporter 2 gene (SLC1A2) with schizophrenia. BMC Psychiatry 4: 21.
Diamond JS (2002). A broad view of glutamate spillover. Nat Neurosci 5: 291–292.
Fattorini G, Melone M, Bragina L, Candiracci C, Cozzi A, Pellegrini Giampietro DE et al (2008). GLT-1 expression and Glu uptake in rat cerebral cortex are increased by phencyclidine. Glia 56: 1320–1327.
Ferguson RE, Carroll HP, Harris A, Maher ER, Selby PJ, Banks RE (2005). Housekeeping proteins: a preliminary study illustrating some limitations as useful references in protein expression studies. Proteomics 5: 566–571.
Ferraguti F, Shigemoto R (2006). Metabotropic glutamate receptors. Cell Tissue Res 326: 483–504.
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001). Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156: 117–154.
Geyer MA, McIlwain KL, Paylor R (2002). Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry 7: 1039–1053.
Geyer MA, Swerdlow NR (1998). Measurement of startle response, prepulse inhibition, and habituation. In: Crawley JN, Skolnick P (eds). Current Protocols in Neuroscience. Wiley: New York. pp 8.7.1–8.7.157.
Harrison PJ (2008). Metabotropic glutamate receptor agonists for schizophrenia. Br J Psychiatry 192: 86–87.
Imre G (2007). The preclinical properties of a novel group II metabotropic glutamate receptor agonist LY379268. CNS Drug Rev 13: 444–464.
Imre G, Salomons A, Jongsma M, Fokkema DS, Den Boer JA, Ter Horst GJ (2006). Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat. Pharmacol Biochem Behav 84: 392–399.
Lauriat TL, McInnes LA (2007). EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders. Mol Psychiatry 12: 1065–1078.
Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A et al (2008). Mechanism of ceftriaxone induction of excitatory amino acid tranporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem 283: 13116–13123.
Lewis DA, Gonzalez-Burgos G (2006). Pathophysiologically based treatment interventions in schizophrenia. Nat Med 12: 1016–1022.
Lewis DA, Moghaddam B (2006). Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63: 1372–1376.
Martinez ZA, Ellison GD, Geyer MA, Swerdlow NR (1999). Effects of sustained phencyclidine exposure on sensorimotor gating of startle in rats. Neuropsychopharmacology 21: 28–39.
Matute C, Melone M, Vallejo-Illarramendi A, Conti F (2005). Increased expression of the astrocytic glutamate transporter GLT-1 in the prefrontal cortex of schizophrenics. Glia 49: 451–455.
McCullumsmith RE, Meador-Woodruff JH (2002). Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology 26: 368–375.
McGhie A, Chapman J (1961). Disorders of attention and perception in early schizophrenia. Br J Med Psychol 34: 103–116.
Melone M, Bellesi M, Conti F (2009a). Synaptic localization of GLT-1a in the rat somatic sensory cortex. Glia 57: 108–117.
Melone M, Bellesi M, Gubbini A, Conti F (2009b). GLT-1 up-regulation enhances the effect of PCP on prepulse inhibition of the startle reflex in adult rats. Schizophr Res 109: 196–197.
Melone M, Bragina L, Conti F (2003). Clozapine-induced reduction of glutamate transport in the frontal cortex is not mediated by GLAST and EAAC1. Mol Psychiatry 8: 12–13.
Melone M, Burette A, Weinberg RJ (2005). Light microscopic identification and immunocytochemical characterization of glutamatergic synapses in brain sections. J Comp Neurol 492: 495–509.
Melone M, Vitellaro-Zuccarello L, Vallejo-Illarramendi A, Perez-Samartin A, Matute C, Cozzi A et al (2001). The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine. Mol Psychiatry 6: 380–386.
Min MY, Rusakov DA, Kullmann DM (1998). Activation of AMPA, kainate, and metabotropic receptors at hippocampal mossy fiber synapses: role of glutamate diffusion. Neuron 21: 561–570.
Minassian A, Feifel D, Perry W (2007). The relationship between sensorimotor gating and clinical improvement in acutely ill schizophrenia patients. Schizophr Res 89: 225–231.
Minelli A, Barbaresi P, Reimer RJ, Edwards RH, Conti F (2001). The glial glutamate transporter GLT-1 is localized both in the vicinity of and at distance from axon terminals in the rat cerebral cortex. Neuroscience 108: 51–59.
Mitchell SJ, Silver RA (2000). Glutamate spillover suppresses inhibition by activating presynaptic mGluRs. Nature 404: 498–502.
Moghaddam B (2004). Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl) 174: 39–44.
Morice E, Billard JM, Denis C, Mathieu F, Betancur C, Epelbaum J et al (2007). Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia. Neuropsychopharmacology 32: 2108–2116.
Nicholls RE, Alarcon JM, Malleret G, Carroll RC, Grody M, Vronskaya S et al (2008). Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility. Neuron 58: 104–117.
Omrani A, Melone M, Bellesi M, Safiulina V, Aida T, Tanaka K et al (2009). Up-regulation of GLT-1 severely impairs LTD at mossy fibres-CA3 synapses. J Physiol 587: 4575–4588.
Ouyang YB, Voloboueva LA, Xu LJ, Giffard RG (2007). Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J Neurosci 27: 4253–4560.
Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV et al (2007). Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13: 1102–1107.
Ralph RJ, Paulus MP, Fumagalli F, Caron MG, Geyer MA (2001). Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists. J Neurosci 21: 305–313.
Rebuelto M, Ambros L, Rubio M (2003). Daily variations in ceftriaxone pharmacokinetics in rats. Antimicrob Agents Chemother 47: 809–812.
Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW et al (1996). Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16: 675–686.
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE et al (2005). Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433: 73–77.
Rusakov DA, Kullmann DM (1998). Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation. J Neurosci 18: 3158–3170.
Rusakov DA, Lehre KP (2002). Perisynaptic asymmetry of glia: new insights into glutamate signalling. Trends Neurosci 25: 492–494.
Scanziani M, Salin PA, Vogt KE, Malenka RC, Nicoll RA (1997). Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors. Nature 385: 630–634.
Shao L, Vawter MP (2008). Shared gene expression alterations in schizophrenia and bipolar disorder. Biol Psychiatry 64: 89–97.
Sheldon AL, Robinson MB (2007). The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem Int 51: 333–355.
Smith RE, Haroutunian V, Davis KL, Meador-Woodruff JH (2001). Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia. Am J Psychiatry 158: 1393–1399.
Swerdlow NR, Braff DL, Geyer MA (2000). Animal models of deficient sensorimotor gating: what we know, what we think we know, and what we hope to know soon. Behav Pharmacol 11: 185–204.
Swerdlow NR, Braff DL, Taaid N, Geyer MA (1994). Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry 51: 139–154.
Swerdlow NR, Geyer MA, Braff DL (2001). Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 156: 194–215.
Swerdlow NR, Light GA, Cadenhead KS, Sprock J, Hsieh MH, Braff DL (2006). Startle gating deficits in a large cohort of patients with schizophrenia: relationship to medications, symptoms, neurocognition, and level of function. Arch Gen Psychiatry 63: 1325–1335.
Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K et al (1997). Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276: 1699–1702.
Testa CM, Friberg IK, Weiss SW, Standaert DG (1998). Immunohistochemical localization of metabotropic glutamate receptors mGluR1a and mGluR2/3 in the rat basal ganglia. J Comp Neurol 390: 5–19.
Tononi G, Edelman GM (2000). Schizophrenia and the mechanisms of conscious integration. Brain Res Brain Res Rev 31: 391–400.
Tzingounis AV, Wadiche JI (2007). Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci 8: 935–947.
Vallejo-Illarramendi A, Torres-Ramos M, Melone M, Conti F, Matute C (2005). Clozapine reduces GLT-1 expression and glutamate uptake in astrocyte cultures. Glia 50: 276–279.
Venables PH (1960). The effect of auditory and visual stimulation on the skin potential response of schizophrenics. Brain 83: 77–92.
Yamashita M, Fukushima S, Shen HW, Hall FS, Uhl GR, Numachi Y et al (2006). Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology 31: 2132–2139.
Zheng K, Scimemi A, Rusakov DA (2008). Receptor actions of synaptically released glutamate: the role of transporters on the scale from nanometers to microns. Biophys J 95: 4584–4596.
Acknowledgements
This study was funded by grants from MIUR and Università Politecnica delle Marche to FC. We gratefully acknowledge A Frontini's assistance with confocal microscopy.
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Bellesi, M., Conti, F. The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats. Neuropsychopharmacol 35, 1253–1260 (2010). https://doi.org/10.1038/npp.2009.225
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DOI: https://doi.org/10.1038/npp.2009.225
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