Neurochemical Research

, Volume 30, Issue 3, pp 371–377

Neurochemical Changes in LPA1 Receptor Deficient Mice – A Putative Model of Schizophrenia

  • Claire Roberts
  • Panida Winter
  • Claire S. Shilliam
  • Zoe A. Hughes
  • Christopher Langmead
  • Peter R. Maycox
  • Lee A. Dawson


LPA1 is a Gi-coupled seven transmembrane receptor with high affinity for the ligand lysophosphatidic acid. We have investigated the effect of targeted deletion at the lpa1 locus on evoked release of amino acids from hippocampal slices, using in vitro superfusion techniques, and evoked 5-HT efflux from the dorsal raphe nucleus, using invitro fast cyclic voltammetry. Superfusion of hippocampal slices revealed that basal levels of tyrosine, aspartate and glutamate release were significantly increased while K+-evoked release of glutamate and GABA were significantly decreased in lpa1(−/−) mice. Fast cyclic voltammetry measurements in the dorsal raphe nucleus demonstrated significant decreases in electrically evoked 5-HT efflux in lpa1(−/−) mice. In summary, these data demonstrate that the lpa1 mutation produces a number of changes in neurotransmitters that have been associated with a schizophrenic-like pathology.


5-HT GABA glutamate release voltammetry 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bilder, R. M. 2001Schizophrenia as a neurodevelopmental disorderCurr. Opin. Psychiatry14915Google Scholar
  2. 2.
    An, S., Dickens, M. A., Bleu, T., Hallmark, O. G., Goetzl, E. J. 1997Molecular cloning of the human Edg2 protein and its identification as a functional cellular receptor for lysophosphatidic acidBiochem. Biophys. Res. Commun231619622PubMedGoogle Scholar
  3. 3.
    Allard, J., Barron, S., Diaz, J., Lubetzki, C., Zalc, B., Schwartz, J-C., Sokoloff, P. 1998A rat G protein-coupled receptor selectively expressed in myelin-forming cellsEur. J. Neurosci1010451053PubMedGoogle Scholar
  4. 4.
    Hecht, J. H., Weiner, J. A., Post, S. R., Chun, J. 1996Ventricular zone gene−1 (vzg−1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortexJ. Cell Biol13510711083PubMedGoogle Scholar
  5. 5.
    Handford, E. J., Smith, D., Hewson, L., McAllister, G., Beer, M. 2001Edg2 receptor distribution in adult rat brainNeuroreport12757760PubMedGoogle Scholar
  6. 6.
    Liu, Y., Wada, R., Yamashita, T., Mi, Y., Deng, C. X., Hobson, J. P., Rosenfeldt, H. M., Nava, V. E., Chae, S. S., Lee, M. J., Liu, C. H., Hla, T., Spiegel, S., Proia, R. L. 2000Edg−1, the G protein-coupled receptor for sphingosine−1-phosphate, is essential for vascular maturationJ. Clin. Invest106939940PubMedGoogle Scholar
  7. 7.
    Fukushima, N., Weiner, J .A., Chun, J. 2000Lysophosphatidic acid (LPA) is a novel extracellular regulator of cortical neuroblast morphologyDev. Biol228618PubMedGoogle Scholar
  8. 8.
    Harrison, S. M., Reavill, C., Brown, G., Brown, J., Cluderay, J. E., Crook, B., Davies, C., Dawson, L. A., Grau, E., Heidbreder, C., Hemmati, P., Hervieu, G., Howarth, A., Hughes, Z., Hunter, A. J., Latcham, J., Pickering, S., Pugh, P., Rogers, D. C., Shilliam, C., Maycox, P. R 2003LPA−1 deficient mice have phenotypic changes observed in psychiatric diseaseMol. Cell Neurosci2411701179PubMedGoogle Scholar
  9. 9.
    Waddington, J. L., Lane, A., Scully, P., Meagher, D., Quinn, J., Larkin, C., O’Callaghan, E. 1999Early cerebro-craniofacial dysmorphogenesis I schizophrenia: a lifetime trajectory model from neurodevelopmental basis to ‚neuroprogressive’ processJ. Psychiatry Res33477489Google Scholar
  10. 10.
    Braff, D. L., Geyer, M. A. 1990Sensorimotor gating and schizophreniaArch. Gen. Psychiatry47181188PubMedGoogle Scholar
  11. 11.
    Geyer, M. A. 1999Assessing prepulse inhibition of startle in wild-type and knockout micePsychopharmacology1471113PubMedGoogle Scholar
  12. 12.
    Emilien, G., Maloteaux, J.-M., Geurts, M., Hoogenberg, K., Cragg, S. 1999Dopamine receptors—physiological understanding to therapeutic intervention potentialPharmacol. Therapeutics84133156Google Scholar
  13. 13.
    Abi-Dargham, A., Laruelle, M., Aghajanian, G. K., Charney, D., Krystal, J. 1997The role of serotonin in the pathophysiology and treatment of schizophreniaJ. Neuropsychiatry Clin. Neurosci9117PubMedGoogle Scholar
  14. 14.
    Benes, F. M., Berretta, S. 2001GABAergic interneurons: implications for understanding schizophrenia and bipolar disorderNeuropsychopharmacology25127CrossRefPubMedGoogle Scholar
  15. 15.
    Lewis, D. A. 2000GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophreniaBrain Res. Rev31270276PubMedGoogle Scholar
  16. 16.
    Ohnuma, T., Augood, S. J., Arai, H., McKenna, P. J., Emson, P. C. 1999Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABAA receptor α−1 subunit mRNA and human GABA transporter−1 (HGAT−1) mRNA expressionNeuroscience93441448PubMedGoogle Scholar
  17. 17.
    Wiesel, F.-A., Andersson, J. L. R., Westerberg, G., Wieselgren, I.-M., Bjerkenstedt, L., Hagenfeldt, L., Langstrom, B. 1999Tyrosine transport is regulated differently in patients with schizophreniaSchizophrenia Res403742Google Scholar
  18. 18.
    Bressan, R. A., Pilowsky, L. S. 2000Imaging the glutamatergic system in vivo – relevance to schizophreniaEur. J. Nucl. Med2717231731PubMedGoogle Scholar
  19. 19.
    Kim, J. S., Kornhuber, H. H., Schmid-Burgk, W., Holzmuller, B. 1980Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophreniaNeurosci. Lett20379382PubMedGoogle Scholar
  20. 20.
    Noorbala, A. A., Akhondzadeh, S., Davari-Ashtiani, R., Amini-Nooshabedi, H. 1999Piracetam in the treatment of schizophrenia: implications for the glutamate hypothesis of schizophreniaJ. Clin. Pharm. Ther24369374PubMedGoogle Scholar
  21. 21.
    Roberts, C. Winter, P. Shilliam, C. S. Atkins, A. R. Hughes, Z. A. Maycox, P. R. and Dawson, L. A. 2003. Neurochemical changes in the LPA-1 Knock-out Mouse. Pages 91-93 J. in Kehr J., K.Fuxe, U. Ungerstedt and T. Svensson (eds.),. Sweden: Karolinska University Press.Google Scholar
  22. 22.
    Roberts, C., Watson, J., Burton, M., Price, G. W., Jones, B. 1996Functional characterisation of the 5-HT terminal autoreceptor in the guinea-pig brain cortexBr. J. Pharmacol117384388PubMedGoogle Scholar
  23. 23.
    Dawson, L. A., Stow, J. M., Palmer, A. M. 1997Improved temporal resolution of microdialysis measurement of glutamate and aspartate using capillary electrophoresis with laser induced fluorescence detectionJ. Chromatogr. B694455460Google Scholar
  24. 24.
    Roberts, C., Price, G. W. 2001Interaction of serotonin autoreceptor antagonists in the rat dorsal raphe nucleus: an in vitro fast cyclic voltammetry studyNeurosci. Lett3004548PubMedGoogle Scholar
  25. 25.
    Harrison, P. J. 1999The neuropathology of schizophrenia: a critical review of the data and their interpretationBrain122593624CrossRefPubMedGoogle Scholar
  26. 26.
    Harrison, P. J., Eastwood, S. L. 2001Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophreniaHippocampus11508519PubMedGoogle Scholar
  27. 27.
    Reynolds, G. P., Czudek, C., Andrews, H. 1990Deficit and hemispheric asymmetry of GABA uptake sites in the hippocampus in schizophreniaBiol. Psychiatry2710381044PubMedGoogle Scholar
  28. 28.
    Benes, F. M., Khan, Y., Vincent, S. L., Wickramasinghe, R. 1996Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brainSynapse22338349CrossRefPubMedGoogle Scholar
  29. 29.
    Jentsch, J. D., Roth, R. H. 1999The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophreniaNeuropsychopharmacology20201225PubMedGoogle Scholar
  30. 30.
    Adler, C. M., Malhorta, A. K., Elman, I., Carson, R., Pickar, D., Breier, A. 1999Effects of NMDA receptor antagonist ketamine on striatal dopamine release in schizophreniaSchizophrenia Res36299Google Scholar
  31. 31.
    Krystal, J. H., Karper, L. P., Seibyl, J. P., Freeman, G. K., Delaney, R., Bremner, J. D., Heninger, G. R., Bowers, M. B., Charney, D. S. 1994Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans —psychotomimetic, perceptual, cognitive, and neuroendocrine responsesArch. Gen. Psychiatry51199214PubMedGoogle Scholar
  32. 32.
    Luby, E. D., Cohen, B. D., Rosembum, G., Gottlieb, J. S., Kelley, R. 1959Study of a new schizophrenomimetic drug SernylArch. Neurol. Psychiatry81363369Google Scholar
  33. 33.
    Lipska, B. K., Weinberger, D. R. 2000To model a psychiatric disorder in animals: Schizophrenia as a reality testNeuropsychopharmacology23223239PubMedGoogle Scholar
  34. 34.
    Swerdlow, N. R., Geyer, M. A., Braff, D. L. 2001Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challengesPsychopharmacology156194215PubMedGoogle Scholar
  35. 35.
    Fletcher, P. J., Phil, D., Selhi, Z. F., Azampanah, A., Sills, T. L. 2001Reduced brain serotonin activity disrupts prepulse inhibition of the acoustic startle reflex: effects of 5,7-dihydroxytryptamine and p-chlorophenylalanineNeuropsychopharmacology24399409PubMedGoogle Scholar
  36. 36.
    Kehne, J. H., Padich, R. A., McCloskey, T. C., Taylor, V. L., Schmidt, C. J. 19965-HT modulation of auditory and visual sensorimotor gating:I. Effects of 5-HT releasers on sound and light prepulse inhibition in Wistar ratsPsychopharmacology12495101PubMedGoogle Scholar
  37. 37.
    Rydin, E., Schalling, D., Asberg, M. 1982Rorschach ratings in depressed patients and suicidal patients with low levels of 5-hydroxyindoleacetic acid in cerebrospinal fluidPsych. Res7229243Google Scholar
  38. 38.
    Hertel, P., Nomikos, G., Iurlo, M., Svensson, T. H. 1996Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brainPsychopharmacology1247486PubMedGoogle Scholar
  39. 39.
    Dursun, S. M., Szemis, A., Andrews, H., Whitaker, P., Revely, M. A. 2000Effects of clozapine and typical antipsychotic drugs on plasma 5-HT turnover and impulsivity in patients with schizophrenia: a cross-sectional studyJ. Psych. Neurosci25347352Google Scholar
  40. 40.
    Dahlstrom, A., Fuxe, K. 1964Evidence for the existence of monoamine containing neurones in the CNSActa Physiol. Scan62155Google Scholar
  41. 41.
    Kosofsky, B. E., Molliver, M. E. 1987The serotonergic innervation of cerebral cortex: different classes of axon terminals arise from dorsal and median raphe nucleiSynapse1153168PubMedGoogle Scholar
  42. 42.
    Azmitia, E. C., Segal, M. 1978An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the ratJ. Comp. Neurol179641668PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Claire Roberts
    • 1
  • Panida Winter
    • 1
  • Claire S. Shilliam
    • 1
  • Zoe A. Hughes
    • 1
  • Christopher Langmead
    • 1
  • Peter R. Maycox
    • 1
  • Lee A. Dawson
    • 1
  1. 1.Psychiatry Centre of Excellence for Drug DiscoveryGlaxoSmithKlineEssexUK

Personalised recommendations