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

Abstract

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 GlyT1 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 M) 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 NMDAR͞␣-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.glutamate ͉ glial cell ͉ memory ͉ prepulse inhibition

P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters

“…cytes and is the main regulator of the glycine levels in glycinergic synapses containing glycine receptors and glutamatergic synapses containing NMDA receptors (5,31,66). In addition to its glial localization, GLYT1 has been found in glutamatergic neurons, although in low abundance (38).…”

Behavioral genetic contributions to the study of addiction-related amphetamine effects

“…Deletion of the GlyT1 glycine transporter caused increased concentrations of glycine at the synapse, and thus an increased ratio of NMDA/AMPA signaling. Animals heterozygous for the GlyT1 deletion showed WT levels of stimulation in response to amphetamine administration, but did not display the normal disruption of PPI exhibited by WT animals (Tsai et al, 2004). This suggests yet another target for consideration in the search for the precise substrates involved in the effects of amphetamines on PPI.…”

Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors

“…[21][22][23] Employing these phenotypic end points, a number of studies have reported 'schizophrenia-related' abnormalities in mice with engineered mutations in various synaptic and downstream signaling components of the glutamate system, including NMDA NR1 receptor, NMDA receptor glycine binding site, mGluR1, mGluR2 and mGluR5 receptors, glycine transporter, calcineurin and Homer1. [24][25][26][27][28][29] Previous studies have demonstrated that GluR1 knockout mice (KO) 30 exhibit behavioral abnormalities on tests for cognition, motor function and responses to drugs of abuse. [30][31][32][33][34][35][36][37] In the present study, we sought to extend these data by assessing these mice for a variety of 'schizophrenia-related' phenotypes.…”