Glycine transporter type 1 blockade changes NMDA receptor‐mediated responses and LTP in hippocampal CA1 pyramidal cells by altering extracellular glycine levels

Martina, Marzia; Gorfinkel, Yelena; Halman, Samantha; Lowe, John; Periyalwar, Pranav; Schmidt, Christopher J.; Bergeron, Richard

doi:10.1113/jphysiol.2004.063321

Cited by 164 publications

(128 citation statements)

References 40 publications

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“…In the central nervous system, the concentration of glycine is tightly regulated by GlyTs (Gomeza et al, 2003). Here, we demonstrated that GlyT1 antagonist-induced blockade of GlyT1 increased the magnitude of NMDAR-dependent LTP induction (Figure 4), which is consistent with reports from several other groups that glycine accumulation facilitates the magnitude of LTP (Martina et al, 2004;Kinney et al, 2003). The LTP induction is usually accompanied by E-S potentiation (Bliss and Lomo, 1973), which leads to increased network activity.…”

Section: Glycine Accumulation Reduces Overall Excitabilitysupporting

confidence: 91%

“…Elevation of extracellular glycine is known to facilitate LTP induction in several brain regions including the hippocampus (Martina et al, 2004;Kinney et al, 2003). To determine whether GlyT1 antagonists elevated extracellular glycine levels under our experimental conditions, we examined their effect on synaptic plasticity in hippocampal slices.…”

Section: Glyt1 Antagonists Facilitated Ltp Inductionmentioning

confidence: 99%

“…GlyT1 blockade increases the extracellular concentration of glycine (Martina et al, 2004), which not only facilitated NMDAR-mediated responses (Figure 4), but also activated GlyRs to induce tonic current ( Figure 5) and E-S depression (Figure 3) in hippocampal CA1 area. However, since no glycinergic neurotransmission has been found in the hippocampus (Mody et al, 1994), from where was this amino acid released?…”

Section: Is Glycine a Gliotransmitter?mentioning

confidence: 99%

“…In the hippocampus, where rare GlyT type 2 (GlyT2) (Jursky and Nelson, 1995) but robust GlyT type 1 (GlyT1) (Zafra et al, 1995) is expressed and colocalized with N-methyl-D-aspartate receptors (NMDAR) (Smith et al, 1992), the blockade of high-affinity GlyT1 modulates NMDAR-mediated responses and long-term potentiation (LTP) by increasing extracellular glycine levels (Martina et al, 2004;Kinney et al, 2003). Several other observations from rat prefrontal cortical neurons (Chen et al, 2003), spinal cord lamina X neurons (Bradaia et al, 2004), and hypoglossal motorneurons (Lim et al, 2004) also support a role of elevated glycine levels in NMDAR activity through GlyT1-dependent processes.…”

Section: Introductionmentioning

confidence: 99%

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Glycine Uptake Regulates Hippocampal Network Activity via Glycine Receptor-Mediated Tonic Inhibition

Zhang

Gong

et al. 2007

Neuropsychopharmacol

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Functional glycine receptors (GlyRs) are enriched in the hippocampus, but their role in hippocampal function remains unclear. Since the concentration of ambient glycine is determined by the presence of powerful glycine transporter (GlyT), we blocked the reuptake of glycine in hippocampal slices to examine the role of GlyRs. Antagonists of GlyT type 1 (GlyT1) but not that of GlyT type 2 (GlyT2) induced excitatory postsynaptic potential (EPSP)-spike depression, which was reversed by the specific GlyR antagonist strychnine. Moreover, endogenously elevating the glycine concentration with the GlyT1 antagonists facilitated NMDA receptor-dependent longterm potentiation induction, and elicited a strychnine-sensitive chloride current. In addition, impairment of glial function with fluoroacetate blocked the effect of GlyT1 antagonists on the EPSP-spike curve. Furthermore, pretreatment with sarcosine was effective in controlling pentylenetetrazol-induced seizures. These results indicate an essential role of GlyTs in fine-tuning tonic activation of GlyRs and suggest a potential role of GlyR-dependent EPSP-spike depression in hippocampal network stability.

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Section: Glycine Accumulation Reduces Overall Excitabilitysupporting

confidence: 91%

Section: Glyt1 Antagonists Facilitated Ltp Inductionmentioning

confidence: 99%

Section: Is Glycine a Gliotransmitter?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Glycine Uptake Regulates Hippocampal Network Activity via Glycine Receptor-Mediated Tonic Inhibition

Zhang

Gong

et al. 2007

Neuropsychopharmacol

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“…Blocking of GLYT1 is known to enhance the activation of NMDA receptor-dependent synaptic transmission [17] and to reduce neuronal signaling [18,19]. Previous reports have suggested that Figure 1.…”

Section: Discussionmentioning

confidence: 99%

Glycine transporter-1 regulates the proliferation of neural stem/progenitor cells derived from the embryonic mouse hippocampus

Yoneyama¹,

Ogita²,

Yamaguchi³

et al. 2017

Glob Drugs Therap

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Effect of Bitopertin, a Glycine Reuptake Inhibitor, on Negative Symptoms of Schizophrenia

et al. 2014

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IMPORTANCE In schizophrenia, the severity of negative symptoms is a key predictor of long-term disability. Deficient signaling through the N-methyl-D-aspartate receptor is hypothesized to underlie many signs and symptoms associated with schizophrenia in particular negative symptoms. Glycine acts as an N-methyl-D-aspartate receptor coagonist. Blockade of the glycine transporter type 1 to inhibit glycine reuptake and elevate synaptic glycine concentrations represents an effective strategy to enhance N-methyl-D-aspartate receptor transmission. OBJECTIVE To determine the efficacy and safety of bitopertin (RG1678), a glycine reuptake inhibitor, in patients with schizophrenia and predominant negative symptoms who were stable while taking an antipsychotic treatment. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled, phase 2 proof-of-concept trial involved 323 patients with schizophrenia and predominant negative symptoms across 66 sites worldwide. INTERVENTIONS Bitopertin (10, 30, or 60 mg/d) or placebo added to standard antipsychotic therapy for a treatment duration of 8 weeks. MAIN OUTCOMES AND MEASURES Change from baseline in the Positive and Negative Syndrome Scale negative factor score. RESULTS In the per-protocol population, 8 weeks of treatment with bitopertin was associated with a significant reduction of negative symptoms in the 10-mg/d (mean [SE] reduction in negative symptoms score, −25% [2%]; P = .049) and 30-mg/d (mean [SE], −25% [2%]; P = .03) bitopertin groups, a significantly higher response rate and a trend toward improved functioning in the 10-mg/d group when compared with placebo (mean [SE], −19% [2%]). Results reached trend-level significance in the intent-to-treat population. Estimates of bitopertin binding to glycine transporter type 1 showed that low to medium levels of occupancy yielded optimal efficacy in patients, consistent with findings in preclinical assays. CONCLUSIONS AND RELEVANCE Bitopertin-mediated glycine reuptake inhibition may represent a novel treatment option for schizophrenia, with the potential to address negative symptoms.

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Glycine transporter type 1 blockade changes NMDA receptor‐mediated responses and LTP in hippocampal CA1 pyramidal cells by altering extracellular glycine levels

Cited by 164 publications

References 40 publications

Glycine Uptake Regulates Hippocampal Network Activity via Glycine Receptor-Mediated Tonic Inhibition

Glycine Uptake Regulates Hippocampal Network Activity via Glycine Receptor-Mediated Tonic Inhibition

Glycine transporter-1 regulates the proliferation of neural stem/progenitor cells derived from the embryonic mouse hippocampus

Effect of Bitopertin, a Glycine Reuptake Inhibitor, on Negative Symptoms of Schizophrenia

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