Gene knockout of glycine transporter 1: Characterization of the behavioral phenotype

被引:163
作者
Tsai, G
Ralph-Williams, RJ
Martina, M
Bergeron, R
Berger-Sweeney, J
Dunham, KS
Jiang, ZC
Caine, SB
Coyle, JT
机构
[1] McLean Hosp, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02178 USA
[2] Wellesley Coll, Wellesley, MA 02481 USA
[3] Ottawa Hlth Res Inst, Ottawa, ON K1Y 4E9, Canada
关键词
glutamate; glial cell; memory; prepulse inhibition;
D O I
10.1073/pnas.0402662101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
N-methyl-D-aspartate receptor (NMDAR) activation requires both the binding of glutamate to its recognition site and occupancy of the strychnine insensitive glycine modulatory site (GMS). Pharmacological studies suggest that the glycine transporter, GlyT1, maintains subsaturating concentrations of glycine at synaptic NMDARs. To characterize further the role of GlyT1, we generated mice in which the gene encoding GIyT1 was inactivated by homologous recombination through insertion of a PGK-Neo cassette in place of exons 2 and 3. Real-time quantitative PCR revealed no transcripts in newborn homozygous [GlyT1(-/-)] mice and a 50% reduction in heterozygous (HZ) [GlyT1(+/-)] mice as compared with WT littermates. The activity of Na+-dependent glycine transport in forebrain homogenates was similarly affected. Homozygous mice died within 12 h of birth. In acute hippocampal slices, exogenous glycine or D-serine (10 muM) enhanced NMDAR currents with Schaffer collateral stimulation in WT mice but not HZ mice, suggesting that the GMS was more occupied in the latter. The NMDAR/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ratio of the excitatory postsynaptic currents was significantly increased in the HZ mice. In the water maze, the HZ mice exhibited better spatial retention. Furthermore, HZ mice were less sensitive to an amphetamine disruption of prepulse inhibition than WT mice but were more sensitive to the effects of MK-801. Thus, reduced expression of GlyT1 enhances hippocampal NMDAR function and memory retention and protects against an amphetamine disruption of sensory gating, suggesting that drugs which inhibit GlyT1 might have both cognitive enhancing and antipsychotic effects.
引用
收藏
页码:8485 / 8490
页数:6
相关论文
共 26 条
  • [1] Modulation of N-methyl-D-aspartate receptor function by glycine transport
    Bergeron, R
    Meyer, TM
    Coyle, JT
    Greene, RW
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) : 15730 - 15734
  • [2] 2 GLYCINE TRANSPORTER VARIANTS WITH DISTINCT LOCALIZATION IN THE CNS AND PERIPHERAL-TISSUES ARE ENCODED BY A COMMON GENE
    BOROWSKY, B
    MEZEY, E
    HOFFMAN, BJ
    [J]. NEURON, 1993, 10 (05) : 851 - 863
  • [3] Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo
    Chen, L
    Muhlhauser, M
    Yang, CR
    [J]. JOURNAL OF NEUROPHYSIOLOGY, 2003, 89 (02) : 691 - 703
  • [4] Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia
    Coyle, JT
    Tsai, G
    Goff, D
    [J]. GLUTAMATE AND DISORDERS OF COGNITION AND MOTIVATION, 2003, 1003 : 318 - 327
  • [5] Danysz W, 1998, PHARMACOL REV, V50, P597
  • [6] Mice are not little rats: species differences in a one-day water maze task
    Frick, KM
    Stillner, ET
    Berger-Sweeney, J
    [J]. NEUROREPORT, 2000, 11 (16) : 3461 - 3465
  • [7] Mouse genetic models for prepulse inhibition: an early review
    Geyer, MA
    McIlwain, KL
    Paylor, R
    [J]. MOLECULAR PSYCHIATRY, 2002, 7 (10) : 1039 - 1053
  • [8] Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review
    Geyer, MA
    Krebs-Thomson, K
    Braff, DL
    Swerdlow, NR
    [J]. PSYCHOPHARMACOLOGY, 2001, 156 (2-3) : 117 - 154
  • [9] Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in Glycinergic inhibition
    Gomeza, J
    Hülsmann, S
    Ohno, K
    Eulenburg, V
    Szöke, K
    Richter, D
    Betz, H
    [J]. NEURON, 2003, 40 (04) : 785 - 796
  • [10] The effect of (±)-CP-101,606, an NMDA receptor NR2B subunit selective antagonist, in the Morris watermaze
    Guscott, MR
    Clarke, HF
    Murray, F
    Grimwood, S
    Bristow, LJ
    Hutson, PH
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 2003, 476 (03) : 193 - 199