Skip to main content
Log in

Reduced Expression of GABA Transporter GAT3 in Helpless Rats, an Animal Model of Depression

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Mood disorders have been linked to glial and synaptic pathology such as disturbed neurotransmission of γ-aminobutyric acid (GABA). We evaluated the expression of GABAergic marker genes in rats with helpless behaviour, an animal model of depression. Male Sprague-Dawley rats from inbred lines were tested for helpless behaviour and grouped according to failures in terminating foot shock currents. Expression levels of GABAergic marker genes were assessed using semiquantitative in situ-hybridization. Animals with congenital helpless behaviour (cH) were unable to escape current exposure in contrast to cH-animals derived from the same litters with low failure rates and to non-helpless animals (cNH). We found a significant downregulation of the GABA transporter GAT3 in cLH rats. GAT1 showed small changes, glutamic acid decarboxylase (GAD67) and the vesicular GABA transporter were not significantly altered. Reduced GABA transporter expression is well in concert with the behavioural phenotypes of knockout animals and strengthens the hypothesis of impaired glial functions in depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455(7215):894–902. doi:10.1038/nature07455

    Article  PubMed  CAS  Google Scholar 

  2. Lee Y, Gaskins D, Anand A, Shekhar A (2007) Glia mechanisms in mood regulation: a novel model of mood disorders. Psychopharmacology 191:55–65. doi:10.1007/s00213-006-0652-4

    Article  PubMed  Google Scholar 

  3. Rajkowska G (2003) Depression: what we can learn from postmortem studies. Neuroscientist 9(4):273–284. doi:10.1177/1073858403252773

    Article  PubMed  Google Scholar 

  4. Bowley MP, Drevets WC, Ongur D, Price JL (2002) Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 52(5):404–412. doi:10.1016/S0006-3223(02)01404-X

    Article  PubMed  Google Scholar 

  5. Ongur D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 95(22):13290–13295. doi:10.1073/pnas.95.22.13290

    Article  PubMed  CAS  Google Scholar 

  6. Kendell SF, Krystal JH, Sanacora G, Kendell SF, Krystal JH, Sanacora G (2005) GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin Ther Targets 9(1):153–168. doi:10.1517/14728222.9.1.153

    Article  PubMed  CAS  Google Scholar 

  7. Henn FA (1976) Neurotransmission and glial cells: a functional relationship? J Neurosci Res 2(4):271–282. doi:10.1002/jnr.490020404

    Article  PubMed  CAS  Google Scholar 

  8. Gosselin RD, Gibney S, OMalley D, Dinan TG, Cryan JF (2009) Region specific decrease in glial fibrillary acidic protein (GFAP) immunoreactivity in the brain of a rat model of depression. Neuroscience 152(2):915–925

    Article  Google Scholar 

  9. Sanacora G, Rothman DL, Mason G, Krystal JH (2003) Clinical studies implementing glutamate neurotransmission in mood disorders. Ann N Y Acad Sci 1003:292–308. doi:10.1196/annals.1300.018

    Article  PubMed  CAS  Google Scholar 

  10. Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G et al (2002) Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 7(Suppl 1):S71–S80. doi:10.1038/sj.mp.4001021

    Article  PubMed  CAS  Google Scholar 

  11. Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP et al (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 102(43):15653–15658. doi:10.1073/pnas.0507901102

    Article  PubMed  CAS  Google Scholar 

  12. Meltzer HY, Fonnum F (1987) Biochemistry, anatomy, and pharmacology of GABA neurons. Psychopharmacology 18:173–182

    Google Scholar 

  13. Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC et al (1990) Cloning and expression of a rat brain GABA transporter. Science 249(4974):1303–1306. doi:10.1126/science.1975955

    Article  PubMed  CAS  Google Scholar 

  14. Gadea A, Lopez-Colome AM (2001) Glial transporters for glutamate, glycine, and GABA: II. GABA transporters. J Neurosci Res 63(6):461–468. doi:10.1002/jnr.1040

    Article  PubMed  CAS  Google Scholar 

  15. Durkin MM, Smith KE, Borden LA, Weinshank RL, Branchek TA, Gustafson EL (1995) Localization of messenger RNAs encoding three GABA transporters in rat brain: an in situ hybridization study. Brain Res Mol Brain Res 33:7–21. doi:10.1016/0169-328X(95)00101-W

    Article  PubMed  CAS  Google Scholar 

  16. Frahm C, Draguhn A (2001) GAD and GABA transporter (GAT-1) mRNA expression in the developing rat hippocampus. Dev Brain Res 132:1–13. doi:10.1016/S0165-3806(01)00288-7

    Article  CAS  Google Scholar 

  17. Chiu CS, Brickley S, Jensen K, Southwell A, Mckinney S, Cull-Candy S et al (2005) GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci 25(12):3234–3245. doi:10.1523/JNEUROSCI.3364-04.2005

    Article  PubMed  CAS  Google Scholar 

  18. Chaudhry FA, Reimer RJ, Bellocchio EE, Danbolt NC, Osen KK, Edwards RH et al (1998) The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J Neurosci 18(23):9733–9750

    PubMed  CAS  Google Scholar 

  19. McIntire SL, Reimer RJ, Schuske K, Edwards RH, Jorgensen EM (1997) Identification and characterization of the vesicular GABA transporter. Nature 389(6653):870–876. doi:10.1038/39908

    Article  PubMed  CAS  Google Scholar 

  20. Emrich HM, von Zerssen D, Kissling W, Moller HJ, Windorfer A (1980) Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders. Arch Psychiatry Neural Disord 229(1):1–16. doi:10.1007/BF00343800

    Article  CAS  Google Scholar 

  21. Petty F (1995) GABA and mood disorders: a brief review and hypothesis. J Affect Disord 34(4):275–281. doi:10.1016/0165-0327(95)00025-I

    Article  PubMed  CAS  Google Scholar 

  22. Petty F, Schlesser MA (1981) Plasma GABA in affective illness. A preliminary investigation. J Affect Disord 3(4):339–343. doi:10.1016/0165-0327(81)90003-3

    Article  PubMed  CAS  Google Scholar 

  23. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC (2007) Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 64(2):193–200. doi:10.1001/archpsyc.64.2.193

    Article  PubMed  CAS  Google Scholar 

  24. Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA et al (1999) Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 56(11):1043–1047. doi:10.1001/archpsyc.56.11.1043

    Article  PubMed  CAS  Google Scholar 

  25. Sanacora G, Mason GF, Krystal JH (2000) Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. Crit Rev Neurobiol 14(1):23–45

    PubMed  CAS  Google Scholar 

  26. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth F, Sule A et al (2007) Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 61:806–812. doi:10.1016/j.biopsych.2006.08.048

    Article  PubMed  CAS  Google Scholar 

  27. Sanacora G, Mason GF, Rothman DL, Hyder F, Ciarcia JJ, Ostroff RB et al (2003) Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 160(3):577–579. doi:10.1176/appi.ajp.160.3.577

    Article  PubMed  Google Scholar 

  28. Sanacora G, Mason GF, Rothman DL, Krystal JH (2002) Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159(4):663–665. doi:10.1176/appi.ajp.159.4.663

    Article  PubMed  Google Scholar 

  29. Carpenter LL, Moreno FA, Kling MA, Anderson GM, Regenold WT, Labiner DM et al (2004) Effect of vagus nerve stimulation on cerebrospinal fluid monoamine metabolites, norepinephrine, and gamma-aminobutyric acid concentrations in depressed patients. Biol Psychiatry 56(6):418–426. doi:10.1016/j.biopsych.2004.06.025

    Article  PubMed  CAS  Google Scholar 

  30. Sanacora G, Fenton LR, Fasula MK, Rothman DL, Levin Y, Krystal JH et al (2006) Cortical gamma-aminobutyric acid concentrations in depressed patients receiving cognitive behavioral therapy. Biol Psychiatry 59(3):284–286. doi:10.1016/j.biopsych.2005.07.015

    Article  PubMed  CAS  Google Scholar 

  31. Roy A (1993) Neuropeptides in relation to suicidal behavior in depression. Neuropsychobiology 28(4):184–186. doi:10.1159/000119021

    Article  PubMed  CAS  Google Scholar 

  32. Sundman-Eriksson I, Allard P (2002) [(3)H]Tiagabine binding to GABA transporter-1 (GAT-1) in suicidal depression. J Affect Disord 71(1–3):29–33. doi:10.1016/S0165-0327(01)00349-4

    Article  PubMed  CAS  Google Scholar 

  33. Fatemi SH, Stary JM, Earle JA, Araghi-Niknam M, Eagan E (2005) GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and reelin proteins in cerebellum. Schizophr Res 72(2–3):109–122. doi:10.1016/j.schres.2004.02.017

    PubMed  Google Scholar 

  34. Cryan JF, Slattery DA (2007) Animal models of mood disorders: recent developments. Curr Opin Psychiatry 20:1–7. doi:10.1097/YCO.0b013e3280117733

    Article  PubMed  Google Scholar 

  35. Czeh B, Simon M, van der Hart MG, Schmelting B, Hesselink MB, Fuchs E (2005) Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: prevention by treatment with a substance P receptor (NK1) antagonist. Neuropsychopharmacology 30(1):67–79. doi:10.1038/sj.npp.1300581

    Article  PubMed  CAS  Google Scholar 

  36. Borsini F, Mancinelli A, D’Aranno V, Evangelista S, Meli A (1988) On the role of endogenous GABA in the forced swimming test in rats. Pharmacol Biochem Behav 29(2):275–279. doi:10.1016/0091-3057(88)90156-6

    Article  PubMed  CAS  Google Scholar 

  37. Talalaenko AN, Pankrat’ev DV, Goncharenko NV (2003) Neurochemical characteristics of the ventromedial hypothalamus in mediating the antiaversive effects of anxiolytics in different models of anxiety. Neurosci Behav Physiol 33(3):255–261. doi:10.1023/A:1022151331354

    Article  PubMed  CAS  Google Scholar 

  38. Malatynska E, De Leon I, Allen D, Yamamura HI (1995) Effects of amitriptyline on GABA-stimulated 36CI- uptake in relation to a behavioral model of depression. Brain Res Bull 37(1):53–59. doi:10.1016/0361-9230(94)00257-6

    Article  PubMed  CAS  Google Scholar 

  39. Fernandez-Teruel A, Escorihuela RM, Boix F, Longoni B, Corda MG, Tobena A (1990) Imipramine and desipramine decrease the GABA-stimulated chloride uptake, and antigabaergic agents enhance their action in the forced swimming test in rats. Neuropsychobiology 23(3):147–152. doi:10.1159/000119442

    Article  PubMed  CAS  Google Scholar 

  40. Heldt SA, Green A, Ressler KJ (2004) Prepulse inhibition deficits in GAD65 knockout mice and the effect of antipsychotic treatment. Neuropsychopharmacology 29(9):1610–1619. doi:10.1038/sj.npp.1300468

    Article  PubMed  CAS  Google Scholar 

  41. Stork O, Yamanaka H, Stork S, Kume N, Obata K (2003) Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice. Genes Brain Behav 2(2):65–70. doi:10.1034/j.1601-183X.2003.00008.x

    Article  PubMed  CAS  Google Scholar 

  42. Stork O, Ji FY, Kaneko K, Stork S, Yoshinobu Y, Moriya T et al (2000) Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65. Brain Res 865(1):45–58. doi:10.1016/S0006-8993(00)02206-X

    Article  PubMed  CAS  Google Scholar 

  43. 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. doi:10.1073/pnas.96.4.1698

    Article  PubMed  CAS  Google Scholar 

  44. Mombereau C, Kaupmann K, Gassmann M, Bettler B, van der Putten H, Cryan JF (2005) Altered anxiety and depression-related behaviour in mice lacking GABAB(2) receptor subunits. NeuroReport 16(3):307–310. doi:10.1097/00001756-200502280-00021

    Article  PubMed  CAS  Google Scholar 

  45. Cai YQ, Cai GQ, Liu GX, Cai Q, Shi JH, Shi J et al (2006) Mice with genetically altered GABA transporter subtype I (GAT1) expression show altered behavioral responses to ethanol. J Neurosci Res 84(2):255–267. doi:10.1002/jnr.20884

    Article  PubMed  CAS  Google Scholar 

  46. Liu GX, Cai GQ, Cai YQ, Sheng ZJ, Jiang J, Mei Z et al (2007) Reduced anxiety and depression-like behaviors in mice lacking GABA transporter subtype 1. Neuropsychopharmacology 32(7):1531–1539. doi:10.1038/sj.npp.1301281

    Article  PubMed  CAS  Google Scholar 

  47. Liu GX, Liu S, Cai GQ, Sheng ZJ, Cai YQ, Jiang J et al (2007) Reduced aggression in mice lacking GABA transporter subtype 1. J Neurosci Res 85(3):649–655. doi:10.1002/jnr.21148

    Article  PubMed  CAS  Google Scholar 

  48. Petty F, Sherman AD (1981) GABAergic modulation of learned helplessness. Pharmacol Biochem Behav 15(4):567–570. doi:10.1016/0091-3057(81)90210-0

    Article  PubMed  CAS  Google Scholar 

  49. Seligman ME, Maier SF (1967) Failure to escape traumatic shock. J Exp Psychol 74(1):1–9. doi:10.1037/h0024514

    Article  PubMed  CAS  Google Scholar 

  50. Sherman AD, Allers GL, Petty F, Henn FA (1979) A neuropharmacologically-relevant animal model of depression. Neuropharmacology 18(11):891–893. doi:10.1016/0028-3908(79)90087-X

    Article  PubMed  CAS  Google Scholar 

  51. Sherman AD, Sacquitne JL, Petty F (1982) Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16(3):449–454. doi:10.1016/0091-3057(82)90451-8

    Article  PubMed  CAS  Google Scholar 

  52. Willner P, Mitchell PJ (2002) The validity of animal models of predisposition to depression. Behav Pharmacol 13(3):169–188

    PubMed  CAS  Google Scholar 

  53. Sartorius A, Vollmayr B, Neumann-Haefelin C, Ende G, Hoehn M, Henn FA (2003) Specific creatine rise in learned helplessness induced by electroconvulsive shock treatment. NeuroReport 14(17):2199–2201. doi:10.1097/00001756-200312020-00013

    Article  PubMed  CAS  Google Scholar 

  54. Henn FA, Vollmayr B (2005) Stress models of depression: forming genetically vulnerable strains. Neurosci Biobehav Rev 29:799–804. doi:10.1016/j.neubiorev.2005.03.019

    Article  PubMed  Google Scholar 

  55. Vollmayr B, Henn FA (2001) Learned helplessness in the rat: improvements in validity and reliability. Brain Res Prot 8:1–7. doi:10.1016/S1385-299X(01)00067-8

    Article  CAS  Google Scholar 

  56. Vollmayr B, Faust H, Lewicka S, Henn FA (2001) Brain-derived-neurotrophic-factor (BDNF) stress response in rats bred for learned helpnessness. Mol Psychiatry 6:471–474. doi:10.1038/sj.mp.4000907

    Article  PubMed  CAS  Google Scholar 

  57. Zink M, Vollmayr B, Gebicke-Härter P, Henn FA, Thome J (2007) Reduced complexin expression in rats bred for learned helplessness. Brain Res 1144:202–208. doi:10.1016/j.brainres.2007.01.066

    Article  PubMed  CAS  Google Scholar 

  58. Shumake J, Gonzalez-Lima F (2003) Brain systems underlying susceptibility to helplessness and depression. Behav Cogn Neurosci Rev 2(3):198–221. doi:10.1177/1534582303259057

    Article  PubMed  CAS  Google Scholar 

  59. Shumake J, Conejo-Jimenez N, Gonzalez-Pardo H, Gonzalez-Lima F (2004) Brain differences in newborn rats predisposed to helpless and depressive behavior. Brain Res 1030(2):267–276. doi:10.1016/j.brainres.2004.10.015

    Article  PubMed  CAS  Google Scholar 

  60. Henn FA, Vollmayr B (2004) Neurogenesis and depression: etiology or epiphenomenon? Biol Psychiatry 56(3):146–150. doi:10.1016/j.biopsych.2004.04.011

    Article  PubMed  Google Scholar 

  61. Shumake J, Poremba A, Edwards E, Gonzalez-Lima F (2000) Congenital helpless rats as a genetic model for cortex metabolism in depression. NeuroReport 11(17):3793–3798. doi:10.1097/00001756-200011270-00040

    Article  PubMed  CAS  Google Scholar 

  62. Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci 8(3):365–371. doi:10.1038/nn1399

    Article  PubMed  CAS  Google Scholar 

  63. Kram ML, Kramer GL, Steciuk M, Ronan PJ, Petty F (2000) Effects of learned helplessness on brain GABA receptors. Neurosci Res 38(2):193–198. doi:10.1016/S0168-0102(00)00157-7

    Article  PubMed  CAS  Google Scholar 

  64. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic press Inc., San Diego

    Google Scholar 

  65. Zink M, Rapp S, Gebicke-Härter P, Henn FA, Thome J (2005) Antidepressants differentially affect expression of complexin I and II RNA in rat hippocampus. Psychopharmacology 181:560–565. doi:10.1007/s00213-005-0017-4

    Article  PubMed  CAS  Google Scholar 

  66. Wojcik SM, Katsurabayashi S, Guillemin I, Friauf E, Rosenmund C, Brose N et al (2006) A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron 50(4):575–587. doi:10.1016/j.neuron.2006.04.016

    Article  PubMed  CAS  Google Scholar 

  67. Cheetham SC, Crompton MR, Katona CL, Parker SJ, Horton RW (1988) Brain GABAA/benzodiazepine binding sites and glutamic acid decarboxylase activity in depressed suicide victims. Brain Res 460(1):114–123. doi:10.1016/0006-8993(88)91211-5

    Article  PubMed  CAS  Google Scholar 

  68. Tsunekawa N, Arata A, Obata K (2005) Development of spontaneous mouth/tongue movement and related neural activity, and their repression in fetal mice lacking glutamate decarboxylase 67. Eur J NeuroSci 21(1):173–178. doi:10.1111/j.1460-9568.2004.03860.x

    Article  PubMed  Google Scholar 

  69. Wu H, Jin Y, Buddhala C, Osterhaus G, Cohen E, Jin H et al (2007) Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles-evidence from GAD65-knockout mice studies. Brain Res 1154:80–83. doi:10.1016/j.brainres.2007.04.008

    Article  PubMed  CAS  Google Scholar 

  70. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA et al (1999) Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 156(5):675–682

    PubMed  CAS  Google Scholar 

  71. Mayberg HS (2007) Defining the neural circuit of depression: towards a new nosology with therapeutic implications. Biol Psychiatry 61:729–730. doi:10.1016/j.biopsych.2007.01.013

    Article  PubMed  Google Scholar 

  72. Rapp S, Baader M, Hu M, Jennen-Steinmetz C, Henn FA, Thome J (2004) Differential regulation of synaptic vesicle proteins by antidepressant drugs. Pharmacogenomics J 4(2):110–113. doi:10.1038/sj.tpj.6500229

    Article  PubMed  CAS  Google Scholar 

  73. Taylor C, Fricker AD, Devi LA, Gomes I (2005) Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways. Cell Signal 17(5):549–557. doi:10.1016/j.cellsig.2004.12.007

    Article  PubMed  CAS  Google Scholar 

  74. Backstrom T, Andersson A, Andree L, Birzniece V, Bixo M, Bjorn I et al (2003) Pathogenesis in menstrual cycle-linked CNS disorders. Ann N Y Acad Sci 1007:42–53. doi:10.1196/annals.1286.005

    Article  PubMed  Google Scholar 

  75. Hosie AM, Wilkins ME, da Silva HM, Smart TG (2006) Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 444(7118):486–489. doi:10.1038/nature05324

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The excellent technical assistance of H. Schamber and E. Roebel is gratefully acknowledged. This study was funded by the Deutsche Forschungsgemeinschaft (SFB 636 B2).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Zink.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zink, M., Vollmayr, B., Gebicke-Haerter, P.J. et al. Reduced Expression of GABA Transporter GAT3 in Helpless Rats, an Animal Model of Depression. Neurochem Res 34, 1584–1593 (2009). https://doi.org/10.1007/s11064-009-9947-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-009-9947-2

Keywords

Navigation