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Exploratory Study of Selected Nucleotide Variants in GRIN1

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Exploratory Study of Selected Nucleotide Variants in GRIN1 Pharmacological Reports (2021) 73:269–277 https://doi.org/10.1007/s43440-020-00192-1 ARTICLE Exploratory study of selected nucleotide variants in GRIN1, GRIN2A and GRIN2B encoding subunits of the NMDA receptor in a targeted group of schizophrenia patients with chronic cognitive impairment Marek Krzystanek1,2 · Marek Asman3 · Joanna Witecka3 · Artur Pałasz4 · Ryszard Wiaderkiewicz4 Received: 23 June 2020 / Revised: 4 November 2020 / Accepted: 8 November 2020 / Published online: 25 November 2020 © The Author(s) 2020 Abstract Background Schizophrenia is a mental disease that afects approximately 1% of the population. Despite over 100 years of research, its pathomechanism has still not been clarifed. Cognitive defcits, which are one of the symptomatic dimensions of schizophrenia, usually appear a few years before the frst psychotic episode. Therefore, this is why they are probably the clinical manifestation of the primary pathomechanism of schizophrenia. It is also supposed that N-methyl-D-aspartate receptor (NMDA-R) insufciency in the prefrontal cortex is responsible for cognitive defcits in schizophrenia. The study aimed to examine whether four selected single nucleotide variants in GRIN1, GRIN2A and GRIN2B encoding NMDA-R subunits, of which two have not been tested before, are linked with the selected clinical phenotype of cognitive dysfunction in schizophrenia. Methods The study included the targeted group of 117 patients diagnosed with schizophrenia, all with cognitive defcits and in symptomatic remission. DNA fragments including the studied polymorphisms of the NMDA receptors subunit genes were amplifed by polymerase chain reaction and subjected to sequencing. Results The study did not confrm the presence of any of the four selected single nucleotide variants in GRIN1, GRIN2A and GRIN2B subunits of NMDA-R. Conclusions The fnding indicates that selected single nucleotide variants in GRIN2A and GRIN2B encoding subunits of the NMDA receptor are not associated with the presence of cognitive defcits in schizophrenia. Keywords Schizophrenia · NMDA receptor · Cognitive defcits · Single nucleotide variants Introduction The pathomechanism of schizophrenia remains an unex- plained mystery of psychiatry. Probably either the etiology * of schizophrenia is complex, or it is a group of diseases with Marek Krzystanek diferent pathomechanisms, clinical picture and prognosis. [email protected] High expectations while solving the puzzle of schizophre- 1 Department and Clinic of Psychiatric Rehabilitation, nia were linked with results of resequencing the human Faculty of Medical Sciences, Medical University of Silesia genome. Unfortunately, the results of genetic testing so far in Katowice, Ziołowa 45/47, 40-635 Katowice, Poland are disappointing. It is estimated that the cumulative efect 2 Department of Psychiatry and Psychotherapy, Faculty of single nucleotide variants (SNVs) explains only about of Medical Sciences, Medical University of Silesia 30% of the genetic risk of developing schizophrenia [1]. in Katowice, Ziołowa 45/47, 40-635 Katowice, Poland 3 Nowadays, more attention is paid to the greater role played Department of Parasitology, Faculty of Pharmaceutical by mechanisms mediating the interaction between environ- Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jedności 8, 41-200 Sosnowiec, Poland mental factors and the regulation of gene expression in the pathogenesis of schizophrenia. 4 Department of Histology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Medyków 18, Since cognitive defcits in schizophrenia manifest several 40-752 Katowice, Poland years before the period of acute psychosis, they are supposed Vol.:(0123456789)1 3 270 M. Krzystanek et al. to be symptoms of the primary pathogenic process of schiz- prepsychotic symptoms of schizophrenia [3]. Then, in ophrenia [2, 3]. In most patients, cognitive defcits begin the period of late adolescence, glutaminergic hyperactiv- 3–4 years before the frst episode of the disease, i.e., in the ity occurs and this condition leads to full-symptomatic prodromal period and do not occur in earlier periods of life schizophrenia [3]. [4]. Furthermore, long-term observations of schizophrenia The insufciency of NMDA receptors is closely asso- indicate chronic persistence of cognitive defcits in patients ciated with the appearance of cognitive dysfunctions and [5, 6]. hypofrontality in schizophrenia [11]. Cognitive disturbances Schizophrenia results from disturbances in the local and in schizophrenia, mainly in the form of attention and work- cortical-subcortical neuronal systems, involving a greater ing memory defcit, result from prefrontal cortex dysfunc- number of brain structure, and one of the components of tion and are associated with glutaminergic transmission the complex pathogenesis of this disease is a dysfunction defciency caused by NMDA-Rs hypofunction [12]. There of N-methyl-D-aspartate receptors (NMDA-Rs, Fig. 1) [7]. is a lot of experimental and clinical evidence confrming the Involvement of NMDA-Rs in the pathogenesis of schizo- glutaminergic hypothesis of schizophrenia and the important phrenia is indicated by the efect of blocking these recep- role NMDA-Rs play in it [13]. In addition, NMDA-R func- tors in healthy volunteers. Administration of NMDA-Rs’ tion may be also responsible for hypofrontality induced by antagonist ketamine causes psychotic, negative and cog- antipsychotics alone [14]. nitive symptoms characteristic of schizophrenia. Simi- Numerous sequence variations, despite previously larly, administration of ketamine to schizophrenic patients reported mutations, were identifed in GRIN1 gene. But increases their psychotic, cognitive and negative symptoms their associations with selected clinical phenotype of [2]. This may indicate that inhibition of NMDA-R activity cognitive defcit in schizophrenia and other psychiatric in the brain is of key importance for the development of cog- syndromes need to be still confrmed. Rice et al. [15] nitive defcits in schizophrenia, while dysregulation of the identifed several variants in the GRIN1 gene, including dopaminergic or serotonergic system is of secondary nature. the promoter region (rs1114620 [1001G-C change]), in The hypothesis of NMDA-R’s defciency as the main patients with schizophrenia (181,500). Begni et al. inves- pathogenetic component responsible for schizophrenia was tigated the potential role of the 1001G-C variant in suscep- proposed by Carlsson [8, 9]. This model is related to the tibility to schizophrenia (181,500) in a study of 139 Italian neurodevelopmental hypothesis of schizophrenia, which patients with schizophrenia and 145 healthy control sub- assumes that glutaminergic disturbances in various areas jects [16]. Sequence analysis revealed that the C allele may of the brain, including the prefrontal cortex, are responsi- alter the consensus sequence for the transcription factor ble for the psychotic, cognitive and emotional symptoms NF-kappa-B (164,011). The frequency of this allele was [10]. According to the neurodevelopmental hypothesis of higher in patients than in control subjects (p = 0.0085). schizophrenia, disruption of glutaminergic system func- The genotype distribution of the C allele was also dif- tion in the developmental period is responsible for the ferent, with p = 0.034; if the C allele was considered Fig. 1 Schematic representation of NMDA receptor molecule anchored in the neural cell membrane. The main binding sites for important ligands (glu- tamate, glycine) and modulators such as zinc ions, polyamines and phencyclidine (PCP) are present in the structure of NR1 and NR2 subunits. The unique magnesium ion-dependent blockage of voltage-gated cati- onic channel plays a crucial role in the NMDAR function 1 3 Exploratory study of selected nucleotide variants in GRIN1, GRIN2A and GRIN2B encoding… 271 dominant, the diference was more signifcant, p = 0.0137. Materials and methods Begni et al. concluded that GRIN1 is a good candidate gene for susceptibility to schizophrenia [16]. Study group Zhao et al. genotyped 5 SNVs in GRIN1 in 2455 schiz- ophrenic and non-schizophrenic Han Chinese subjects, A targeted group of patients diagnosed with schizophrenia including population- and family-based samples, and per- (according to ICD-10 criteria and DSM-IV) was selected formed case–control and transmission disequilibrium test for the study. All patients were Caucasian. The group (TDT) analyses [17]. A highly signifcant association with constituted a selected clinical phenotype of patients suc- schizophrenia was detected at the 5-prime end of GRIN1. cessfully treated for schizophrenia who, despite treatment, Analysis of single variants and multiple-locus haplo- still have cognitive impairment. Patients were recruited in types indicated that the association is mainly generated by mental health outpatient’s clinics and psychiatric wards rs11146020 (case–control study: p = 0.0000013, OR = 0.61, in the years 2007–2011. The study included patients who 95% CI 0.50–0.74; TDT: p = 0.0019, T/NT = 79/123). met the criteria of the clinical phenotype established in the Therefore, in this work, we decided to look for another not study: the presence of cognitive impairment despite symp- studied yet variant in the sequence of GRIN1, rs11146020/ tomatic remission of schizophrenia. All patients enrolled NG_011507.1:g.4476G > C/5′UTR in association with in the study met the following symptomatic remission cri- the selected clinical phenotype of cognitive deficit in
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