Skip to main content

Abnormalities in extracellular glycine and glutamate levels in the striatum of sandy mice

  • Yuji Kitaichi (a1), Ryota Hashimoto (a2) (a3) (a4), Takeshi Inoue (a1), Tomohiro Abekawa (a1), Aya Kakuta (a1), Satoko Hattori (a4) and Tsukasa Koyama (a1)...

Glycine regulates glutamatergic neurotransmission, and several papers have reported the relationship between glycine and schizophrenia. The dysbindin-1 (DTNBP1: dystrobrevin-binding protein 1) gene is related to glutamatergic neurotransmission and has been found to be a strong candidate gene for schizophrenia. In this study, we clarified the relationship between dysbindin, glutamate, and glycine with in vivo microdialysis methods.


We measured extracellular glycine and glutamate levels in the striatum of sandy (sdy) mice using in vivo microdialysis methods. Sdy mice express no dysbindin protein owing to a deletion in the dysbindin-1 gene. In addition, we measured changes in those amino acids after methamphetamine (METH) administration.


The basal levels of extracellular glycine and glutamate in the striatum of sdy mice were elevated. These extracellular glutamate levels decreased gradually after METH administration and were not subsequently different from those of wild-type mice.


These results suggest that dysbindin might modulate glycine and glutamate release in vivo.

Corresponding author
Dr. Ryota Hashimoto, Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. Tel: +81-6-6879-3074; Fax: +81-6-6879-3074; E-mail:
Hide All
1.Yang CR, Svensson KA. Allosteric modulation of NMDA receptor via elevation of brain glycine and d-serine: the therapeutic potentials for schizophrenia. Pharmacol Ther 2008;120:317332.
2.Javitt DC. Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci 2010;47:416.
3.Hons J, Zirko R, Ulrychova M, Cermakova E, Doubek P, Libiger J. Glycine serum level in schizophrenia: relation to negative symptoms. Psychiatry Res 2010;176:103108.
4.Labrie V, Lipina T, Roder JC. Mice with reduced NMDA receptor glycine affinity model some of the negative symptoms of schizophrenia. Psychopharmacology (Berl) 2008;200:217230.
5.Kanahara N, Shimizu E, Ohgake Set al. Glycine and d-serine, but not d-cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801. Psychopharmacology (Berl) 2008;198:363374.
6.Allen NC, Bagade S, McQueen MBet al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 2008;40:827834.
7.Talbot K, Eidem WL, Tinsley CLet al. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 2004;113:13531363.
8.Weickert CS, Straub RE, McClintock BWet al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 2004;61:544555.
9.Hashimoto R, Noguchi H, Hori Het al. A genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls. World J Biol Psychiatry 2010;11:431438.
10.Hashimoto R, Noguchi H, Hori Het al. Association between the dysbindin gene (DTNBP1) and cognitive functions in Japanese subjects. Psychiatry Clin Neurosci 2009;63:550556.
11.Olgiati P, Mandelli L, Lorenzi Cet al. Schizophrenia: genetics, prevention and rehabilitation. Acta Neuropsychiatr 2009;21:109120.
12.Hattori S, Murotani T, Matsuzaki Set al. Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Biochem Biophys Res Commun 2008;373:298302.
13.Takao K, Toyama K, Nakanishi Ket al. Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Mol Brain 2008;1. doi:10.1186/1756-6606-1-11.
14.Nihonmatsu-Kikuchi N, Hashimoto R, Hattori Set al. Reduced rate of neural differentiation in the dentate gyrus of adult dysbindin null (sandy) mouse. PLoS One 2011;6:e15886.
15.Kobayashi K, Umeda-Yano S, Yamamori H, Takeda M, Suzuki H, Hashimoto R. Correlated alterations in serotonergic and dopaminergic modulations at the hippocampal mossy fiber synapse in mice lacking dysbindin. PLoS One 2011;6:e18113.
16.Nagai T, Kitahara Y, Shiraki Aet al. Dysfunction of dopamine release in the prefrontal cortex of dysbindin deficient sandy mice: an in vivo microdialysis study. Neurosci Lett 2010;470:134138.
17.Numakawa T, Yagasaki Y, Ishimoto Tet al. Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 2004;13:26992708.
18.Kishimoto M, Ujike H, Motohashi Yet al. The dysbindin gene (DTNBP1) is associated with methamphetamine psychosis. Biol Psychiatry 2008;63:191196.
19.Abekawa T, Ito K, Nakagawa S, Nakato Y, Koyama T. Olanzapine and risperidone block a high dose of methamphetamine-induced schizophrenia-like behavioral abnormalities and accompanied apoptosis in the medial prefrontal cortex. Schizophr Res 2008;101:8494.
20.Ito K, Abekawa T, Koyama T. Relationship between development of cross-sensitization to MK-801 and delayed increases in glutamate levels in the nucleus accumbens induced by a high dose of methamphetamine. Psychopharmacology (Berl) 2006;187:293302.
21.Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. San Diego: Academic Press, 2001.
22.Abekawa T, Ito K, Koyama T. Role of the simultaneous enhancement of NMDA and dopamine D1 receptor-mediated neurotransmission in the effects of clozapine on phencyclidine-induced acute increases in glutamate levels in the rat medial prefrontal cortex. Naunyn Schmiedebergs Arch Pharmacol 2006;374:177193.
23.Chefer VI, Shippenberg TS. Paradoxical effects of prodynorphin gene deletion on basal and cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens. Eur J Neurosci 2006;23:229238.
24.Feng YQ, Zhou ZY, He Xet al. Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. Schizophr Res 2008;106:218228.
25.Hikita T, Taya S, Fujino Yet al. Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia-related protein. J Neurochem 2009;110:15671574.
26.Legendre P. The glycinergic inhibitory synapse. Cell Mol Life Sci 2001;58:760793.
27.Perry KW, Falcone JF, Fell MJet al. Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas. Neuropharmacology 2008;55:743754.
28.Labrie V, Clapcote SJ, Roder JC. Mutant mice with reduced NMDA-NR1 glycine affinity or lack of d-amino acid oxidase function exhibit altered anxiety-like behaviors. Pharmacol Biochem Behav 2009;91:610620.
29.Shimazaki T, Kaku A, Chaki S. d-Serine and a glycine transporter-1 inhibitor enhance social memory in rats. Psychopharmacology (Berl) 2010;209:263270.
30.Gaspar PA, Bustamante ML, Silva H, Aboitiz F. Molecular mechanisms underling glutamatergic dysfunction in schizophrenia: therapeutic implications. J Neurochem 2009;111:891900.
31.Abekawa T, Ohmori T, Koyama T. Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens. Brain Res 1994;643:276281.
32.Karlsgodt KH, Robleto K, Trantham-Davidson Het al. Reduced dysbindin expression mediates N-methyl-d-aspartate receptor hypofunction and impaired working memory performance. Biol Psychiatry 2011;69:2834.
33.Dyck B, Guest K, Sookram C, Basu D, Johnson R, Mishra RK. PAOPA, a potent analogue of Pro–Leu–glycinamide and allosteric modulator of the dopamine D2 receptor, prevents NMDA receptor antagonist (MK-801)-induced deficits in social interaction in the rat: implications for the treatment of negative symptoms in schizophrenia. Schizophr Res 2011;125:8892.
34.Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A. Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 2009;34:15781589.
35.Nestler EJ, Hyman SE, Malenka RC, eds. Molecular neuropharmacology: a foundation for clinical neuroscience. New York: McGraw Hill, 2001.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Acta Neuropsychiatrica
  • ISSN: 0924-2708
  • EISSN: 1601-5215
  • URL: /core/journals/acta-neuropsychiatrica
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 1
Total number of PDF views: 12 *
Loading metrics...

Abstract views

Total abstract views: 230 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st February 2018. This data will be updated every 24 hours.