&lt;p&gt;Association study of the excitatory amino acid transporter 2 (EAAT2) and glycine transporter 1 (GlyT1) gene polymorphism with schizophrenia in a Polish population&lt;/p&gt;

Merk, Wojciech; Kucia, Krzysztof; Medrala, Tomasz; Kowalczyk, Małgorzata; Owczarek, Aleksander; Kowalski, Jan

doi:10.2147/ndt.s194924

Cited by 9 publications

(9 citation statements)

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“…These authors detected three silent mutations in the coding region, C894T in exon 5, C1134T in exon 7, and C1476T in exon 9 (202), highlighting that a role of these variants in the pathogenesis of SCZ is unlikely. Similarly, subsequent case-controls studies confirmed these negative findings (203)(204)(205)(206). Another negative finding derived from a gene expression analysis in post-mortem dorsolateral prefrontal cortex and cerebellum brain samples (207).…”

Section: Genetics Of Glycinergic Pathway In Schizophreniamentioning

confidence: 65%

“…The authors performed two proofof-principle clinical trials with glycine and d-cycloserine obtaining an additional 20 to 26% reduction in symptom severity with the former and 13 to 30% reduction with the latter (201) Conversely, a series of negative studies do not appear to support a role for glycine transmission and signaling in SCZ molecular pathophysiology, at least on genetics ground. (202)(203)(204)(205)(206). The study of Feng et al (202) explored the role of genetic mutations within the glycine receptor a2 subunit gene (GLRA2) in SCZ, using a sequencing approach.…”

Section: Genetics Of Glycinergic Pathway In Schizophreniamentioning

confidence: 99%

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Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

Bartolomeis¹,

Manchia

Marmo³

et al. 2020

Front. Psychiatry

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Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamineglutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a coagonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.

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Section: Genetics Of Glycinergic Pathway In Schizophreniamentioning

confidence: 65%

Section: Genetics Of Glycinergic Pathway In Schizophreniamentioning

confidence: 99%

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

Bartolomeis¹,

Manchia

Marmo³

et al. 2020

Front. Psychiatry

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“…As far as we know, only a few studies on genetic polymorphism of SLC1A2 in MDD were conducted. The majority of studies reported an association of SLC1A2 SNPs with bipolar disorder [46,47,48,49] and schizophrenia [50,51,44]. One of the polymorphisms (-181 A/C, rs4354668) evaluated in this paper was also analyzed in a Thai sample of 100 patients with MDD with and without suicide attempt [52].…”

Section: Discussionmentioning

confidence: 99%

“…Purity and concentration of DNA extracts was assessed using a BioPhotometer plus (Eppendorf AG, Germany). The genotyping of SNPs: rs4354668 A/C in the SLC1A2 and rs2486001 G/A in the SLC6A9 was performed by PCR-RFLP method as described previously [44], using the following published primers: SLC1A2 forward 5'-GAGCGGCGGGGCCTCTTTTC-3' and reverse 5'-TGCAGCCGCTGCCACCTGTG-3' [45], SLC6A9 forward 5'-TTCTATTCCCTGGGGTTCAGCA-3' and reverse 5'-AGCCTGGGCTGAGGCACACCAC-3' [43]. Ampli ed products were digested by two restriction enzymes (BcnI -rs4354668 and AvaII -rs2486001) (Thermo Fisher Scienti c), according to the protocol, and digested products were separated by electrophoresis in 2% agarose gels stained with ethidium bromide.…”

Section: Patient and Control Groups Pro Lementioning

confidence: 99%

Association Study of the SLC1A2 (rs4354668), SLC6A9 (rs2486001) and SLC6A5 (rs2000959) Polymorphisms in Major Depressive Disorder

Rodek

Kowalczyk

Kowalski

et al. 2021

Preprint

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Background: In recent years, a growing body of evidence highlights a causal link between glutamate and depression. The membrane excitatory amino acid transporter 2 (EAAT2), encoded by SLC1A2 is responsible for the uptake and redistribution of most of the synaptic glutamate. Glycine, an inhibitory neurotransmitter, acts as an obligatory co-agonist of N-methyl-D-aspartate (NMDA) receptors and modulates excitatory neurotransmission. The clearance of synaptic glycine is performed by glycine transporters encoded by SLC6A9 and SLC6A5. Higher synaptic glycine and glutamate levels could enhance the activation of NMDA receptors, therefore counteract the hypofunction of glutamate neurotransmission described in major depressive disorder (MDD). The aim of the study was to assess whether polymorphisms of SCL1A2, SCL6A5 and SCL6A9 play a role in the development of MDD and its clinical picture in the Polish population. Methods: The study group consisted of 161 unrelated Caucasian patients with MDD, and 462 healthy controls. Polymorphisms of SLC1A2, SLC6A5 and SLC6A9 were genotyped with PCR-RLFP and TaqMan assays. The relationship between the studied single nucleotide polymorphisms (SNPs) was assessed based on the comparison of genotype and allele distribution in the study and the control group. The research also evaluated the relationships between the studied polymorphisms and clinical variables such as age of disease onset, number of episodes, duration of depression or severity of symptoms.Results: We found a statistically significant association between SLC1A2 rs4354668 polymorphism and MDD development (the frequency of rs4354668 CC genotype and allele C was 2-fold higher in patients than in the control). Such associations were not detected for SLC6A5 and SLC6A9 polymorphisms. No statistically significant impact of the studied SNPs on clinical variables of MDD was also observed. Conclusions: The results of the current study indicate an association of rs4354668 polymorphism in SCL1A2 with depression development in Polish population. Further studies with larger samples should be performed in the future to clarify the current findings.

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“…However, in consideration of the etiology and pathophysiology of schizophrenia, no evidence has supported a proposal that GlyT1 is overexpressed in the brains of schizophrenic patients. In contrast, a series of negative findings of association studies have revealed that neither glycine transmission nor GlyT1 is implicated in the pathogenesis of schizophrenia (228)(229)(230). As described previously, although concentrations of glycine are 10-fold higher than D-serine, D-serine is considered the dominant endogenous coagonist of NMDARs and a modulator of NMDAR-related neurotoxicity (20,21).…”

Section: Non-sarcosine-based Glyt1 Inhibitorsmentioning

confidence: 92%

Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia

et al. 2021

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Schizophrenia is a severe mental illness that affects ~1% of the world's population. It is clinically characterized by positive, negative, and cognitive symptoms. Currently available antipsychotic medications are relatively ineffective in improving negative and cognitive deficits, which are related to a patient's functional outcomes and quality of life. Negative symptoms and cognitive deficits are unmet by the antipsychotic medications developed to date. In recent decades, compelling animal and clinical studies have supported the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia and have suggested some promising therapeutic agents. Notably, several NMDAR-enhancing agents, especially those that function through the glycine modulatory site (GMS) of NMDAR, cause significant reduction in psychotic and cognitive symptoms in patients with schizophrenia. Given that the NMDAR-mediated signaling pathway has been implicated in cognitive/social functions and that GMS is a potential therapeutic target for enhancing the activation of NMDARs, there is great interest in investigating the effects of direct and indirect GMS modulators and their therapeutic potential. In this review, we focus on describing preclinical and clinical studies of direct and indirect GMS modulators in the treatment of schizophrenia, including glycine, D-cycloserine, D-serine, glycine transporter 1 (GlyT1) inhibitors, and D-amino acid oxidase (DAO or DAAO) inhibitors. We highlight some of the most promising recently developed pharmacological compounds designed to either directly or indirectly target GMS and thus augment NMDAR function to treat the cognitive and negative symptoms of schizophrenia. Overall, the current findings suggest that indirectly targeting of GMS appears to be more beneficial and leads to less adverse effects than direct targeting of GMS to modulate NMDAR functions. Indirect GMS modulators, especially GlyT1 inhibitors and DAO inhibitors, open new avenues for the treatment of unmet medical needs for patients with schizophrenia.

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<p>Association study of the excitatory amino acid transporter 2 (EAAT2) and glycine transporter 1 (GlyT1) gene polymorphism with schizophrenia in a Polish population</p>

Cited by 9 publications

References 58 publications

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

Association Study of the SLC1A2 (rs4354668), SLC6A9 (rs2486001) and SLC6A5 (rs2000959) Polymorphisms in Major Depressive Disorder

Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia

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