ISSN: 2640-7744
Scientific Journal of Genetics and Gene Therapy
Research Article       Open Access      Peer-Reviewed

Transcription Factors in Schizophrenia: A Current View of Genetic Aspects

Roksana Zakharyan*

Laboratory of Human Genomics and Immunomics, Institute of Molecular Biology of the National Academy of Sciences of the Republic of Armenia (NAS RA), Yerevan, Armenia
*Corresponding author: Roksana Zakharyan, PhD, Researcher, Laboratory of Human Genomics and Immunomics, Institute of Molecular Biology of the National Academy of Sciences of the Republic of Armenia (NAS RA), 7 Hasratyan St., 0014, Yerevan, Armenia, Tel: + 37410 281540; Fax: + 37410282061; E-mail: r_zakharyan@mb.sci.am
Received: 27 December, 2016 | Accepted: 29 December, 2016 | Published: 30 December, 2016
Keywords: Transcription factor; Gene expression; Single nucleotide polymorphism; PCR-SSP; Schizophrenia; Genetic variant

Cite this as

Zakharyan R (2016) Transcription Factors in Schizophrenia: A Current View of Genetic Aspects. Scientific J Genet Gene Ther 2(1): 017-021. DOI: 10.17352/sjggt.000010

Background: Schizophrenia is a polygenic mental disorder with about 80% heritability. Growing evidence indicated that synaptic dysfunctions contribute to SCZ etiopathogenesis.

The context and purpose of the study: Transcription factors play an important role in the regulation of gene expression. Whereas expression analysis of transcription factor has been performed, studies of their genetic variants are limited. The current review article summarizes data on transcription factors early growth response 3 (EGR3), c-fos transcription (FOS), immune early response 5 (IER5), c-jun (JUN), Nk2 Homeobox 1 (NKX2-1), and transcription factor 4 (TCF4) encoding genes in schizophrenia.

Results and main findings: An important role of the mentioned genes in this pathology has been identified.

Conclusions: We concluded that the genetic variants of the transcription factor encodng genes might contribute to the assessment of disease susceptibility and can find potential use for the development of genetically-driven diagnostic approaches in the future.

Abbreviations

EGR3: Early Growth Response 3 Encoding Gene; FOS: C-Fos Transcription Factor Encoding Gene; IER5: Immune Early Response 5 Transcription Factor Encoding Gene; JUN: C-Jun Transcription Factor Encoding Gene; NKX2-1: Nk2 Homeobox 1 Encoding Gene; PCR-SSP: Polymerase Chain Reaction with Allele-Specific Primers; SCZ: Schizophrenia; TCF4: Transcription Factor 4 Encoding Gene

Background

Schizophrenia is a polygenic mental disorder with the estimated prevalence of 1% in general population and high heritability up to 80% [1]. Despite the results from a number of genome-wide and genetic association studies performed indicating an important role of several genes involved in immune response, neuronal development, apoptosis [2-6], the vast majority of heritable factors is still unclear. Transcription factors and their genetic variants are of special interest in the temrs of genetic component of schizophrenia development. It is well known that transcription factors are essential regulators of gene expression, and perform their function due to specific interaction with transcription factor binding sites located in the promoter region [7]. So far, Maurano et al. (2012) has shown that common single nucleotide polymorphisms (SNPs) are systematically enriched in transcription factor binding sites, especially, those active during fetal development [8]. While expression levels of some transcriptions factors have been partly studied [9-11], their genetic variants are relatively less studied in terms of schizophrenia [12].

The present review summarizes current findings concerning transcription factors in the pathogenesis of schizophrenia at both molecular and genetic levels.

Materials and Methods

An electronic literature search of peer-reviewed English language articles focused on transcription factors and schizophrenia using Pubmed was undertaken.

Transcription factor 4 (TCF4) in schizophrenia

Transcription factor 4 (TCF4, GeneBank ID: 6925) belongs to the superfamily of basic Helix-Loop-Helix (bHLH) transcription factors which acts as a transcriptional repressor or activator of gene expression [13]. A recent genome-wide association study has identified that TCF4 is located in the genetic region considered as a risk factor for schizophrenia [14]. Animal studies suggested that Tcf4-deficient mice demonstrate abnormal brain development suggestting that TCF4 gene expression might also affect brain networks involved in the cognitive functioning and processing [14]. In order to evaluate the potential association of genetic polymorphisms of TCF4 with cognitive deficit in schizophrenia, Hui et al., (2015) performed a case-control study in Han Chinese population [15]. Assessment of disease symptoms using the Positive and Negative Syndrome Scale (PANSS) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) suggested that a allele of the TCF4 gene rs2958182 single nucleotide polymorphism (SNP) is a risk allele of schizophrenia, and is associated with lower cognitive performance in schizophrenia patients as well as delayed memory in controls [15]. By contrast, the earlier study performed in the same population has identified T allele as being associated with better performance of cognitive tasks in patients with schizophrenia but with worse performance in controls [16]. The results from expression analyses showed that mRNA expression level of TCF4 is elevated in neurons derived from human-induced pluripotential stem cells of schizophrenia patients compared to those in healthy subjects [17]. Concerning the relevance to clinical symptoms, a recent pharmacogenetic study has revealed that TCF4 does not affect the improvement of disease symptoms during the treatment with antipsychotics [18]. However, it has been shown that the carriers of disease-associated TCF4 gene rs9960767 allele had better recognition and information processing skills [18] suggesting an important contribution of TCF4 to the pathogenesis of schizophrenia.

Early growth response 3 (EGR3) in schizophrenia

Early growth response 3 gene (EGR3, GeneBank ID: 1960) encodes a transcriptional regulator belonging to the EGR family of CysCysHisCys (C2HC)-type zinc-finger proteins. It has been shown that EGR3 is an immediate-early growth response gene and participates in the transcriptional regulation of genes involved in biological rhythm control. A variety of functions of EGR3 such as participation in lymphocyte development, endothelial cell growth and migration as well neuronal development including regulation of synaptic proteins and synaptic plasticity has been shown [19,20]. Together with other immediate early gene transcription factors, EGR3 is activated in the brain in response to environmental stimuli and regulate downstream neuronal gene expression [20,21].

Genetic association studies performed in different populations have demonstrated important role of EGR3 gene SNPs in the pathogenesis of schizophrenia [22-25]. Results from the Japanese study confirmed for 1140 independent case-control samples demonstrated that IVS1+607(A/G) (rs35201266) SNP has the strongest evidence for disease association [22]. Kim et al., (2010) reported that among the four examined SNPs of the EGR3 gene the rs35201266 has a significant association with schizophrenia [23] that is in concordance with the previously reported data for the same population [22]. Moreover, it has been shown that the “T-G-C-G” haplotype of the rs1008949, rs7009708, rs35201266, and rs3750192 SNPs is overrepresented in patients with schizophrenia compared to controls [23]. A meta-analysis performed by Zhang et al., (2012) revealed a statistically significant association between schizophrenia and rs35201266 polymorphism of the EGR3 gene [24]. Later, Nishamara et al., (2014) has provided in vivo human evidence of a significant effect of the EGR3 gene polymorphisms (namely, rs35201266) on prefrontal hemodynamic activation level in healthy adults and schizophrenia patients. These data suggest that EGR3 may affect prefrontal function through neurodevelopment [20]. So far, in a pooled study of biological pathways of schizophrenia risk it has been shown that the EGR3 gene rs1877670 SNP is associated with disease [25]. Further, Willams et al., (2012) using a pharmacological approach has found that the locomotor suppressive effects of clozapine in Egr3(-/-) deficient mice is specific to second-generation antipsychotics while the first-generation medications suppress the locomotor activity of Egr3(-/-) and wild type mice to a similar degree [26]. Moreover, as the deficit in cortical serotonin 2A receptor (5HT(2A)R) in Egr3(-/-) mice aligns with reports on decreased 5HT(2A)R levels in the brains of schizophrenia patients suggesting a potential mechanism by which putative dysfunction in EGR3 in humans might affect the risk of schizophrenia development [26].

Nk2 Homeobox 1 (NKX2-1) gene in schizophrenia

Nk2 Homeobox 1 gene (NKX2-1, GeneBank ID: 7080) encodes a protein also known as a thyroid-specific transcription factor which binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes and those relevant to somatic symptoms common for schizophrenia [27]. NKX2-1 also plays a central role in the neurodevelopment and is essential for the formation and function of subgroups of neurons, glia, and functional neural networks affected in schizophrenia. It is well known that NKX2-1 expressing striatal GABAergic interneurons mainly contain parvalbumin (PV) [28] and it has been suggested that striatal PV+ interneurons play an important role in the behavioral effects mediated by antipsychotic drugs [29]. Moreover, a number of mice studies confirm the influence of striatal PV+ interneurons on schizophrenia [30,31]. This transcription factor also interacts with several susceptibility genes for schizophrenia, and is involved in gene-environment interactions with neurodevelopmental implications. Findings from families affected by inactivating mutations in NKX2-1 suggested that they may result in brain-lung-thyroid disease, also known as benign hereditary chorea, characterized by impaired coordination, delayed speech development, neonatal pulmonary distress, and congenital hypothyroidism [32].

Myelin transcription factor 1-like (MYT1L) gene in schizophrenia

The myelin transcription factor 1-like gene (MYT1L, GeneBank ID: 23040) coding protein regulates proliferation and differentiation of oligodendrocytes and neural transcription [33,34]. Romm et al. (2005) has found that MYT1L is mainly expressed in the developing central nervous system (CNS) [34]. Among other pathologies, rare genetic variations of this gene have been linked to schizophrenia as well [35]. Later, Li et al., (2012) has examined six SNPs of the MYT1L gene in a Han Chinese population and has found that the rs17039584 polymorphism significantly associates with schizophrenia [36]. Up to date, there is lack of data suggesting implication of MYT1L gene SNPs in pharmacogenetics of schizophrenia; however, functions of the corresponding protein imply its putative significance in the terms of this disease.

Transcription factors cFos, cJun, and Ier5

Transcription factors cFos, cJun, and Ier5 participate in the regulation of numerous processes in human and higher animals, including those associated with neuronal plasticity and immune response. It has been shown that cFos is directly involved in learning and memory mechanisms and the lack of the cFos encoding gene in mice leads to impaired the long-term memory and synaptic transmission [37], the functional activity of which is also usually altered in schizophrenia [38]. Besides, cFos mediates cell response to mitogenic signals, which play a central role in neuron growth and differentiation, as well as in the formation of neural networks [39], typically altered in schizophrenia [40-42]. Experimental data from animal models of schizophrenia also suggest that FOS variants may contribute to the pathogenesis of schizophrenia [43-45]. Thus, it has been shown that fos gene expression is associated with significant weight gain [46].

Transcription factor AP1 formed by these two interacting proteins [47] enhances the transcription of genes the products of which are involved in a number of processes, including the formation of neuronal plasticity and longterm memory [48,49]. AP1 participates in the biogenesis of synaptic vesicles [49], in the assembly of their membranes [40], in the receptor transfer to dendrites [41] as well as controls cell differentiation, proliferation, and apoptosis [42]. Impaired functional activity of AP1 was observed in different diseases of the CNS, brain damage, cognitive deficit, and aging [43-46]. Postmortem brain studies showed that patients with schizophrenia had elevated FOS and JUN RNA levels in the thalamus, the structure that performs processing and integration of nearly all signals that the cortex receives the spinal cord, the midbrain, the cerebellum, and basal ganglions of the brain [47]. AP1 and cFos are also involved in the regulation of immune response: AP1 mediates the expression of proinflammatory cytokines [48], while cFos regulates cytokine expression by mast cells [49].

Up to date, there is lack of information concerning the role of the genetic variants of these transcription factors in schizophrenia. Moreover, no pharmacogenetic approach was used to study the effect of antipsychotic medications depending on the FOS, JUN, and IER5 genetic variants. Our recent findings have identified three genetic variants associated with susceptibility to disease [50]. Thus, we have found that the FOS rs1063169, FOS rs7101, JUN rs11688, and IER5 rs6425663 polymorphisms were associated with schizophrenia. In particular, the risk of schizophrenia was decreased in carriers of the minor alleles FOS rs1063169*T, JUN rs11688*A, and IER5 rs6425663*T, but increased in carriers of the FOS rs7101*T minor variant, especially in homozygotes [50].

Conclusion

This paper suggested the important role of transcription factors in the pathogenesis of schizophrenia. Based upon current findings we may suppose that as the most important players in the genetics of schizophrenia could be nominated transcription factors TCF4, EGR3, NKX2-1 as well as FOS, JUN, IER5 because SNPs in these genes are associated either with disease or its symptoms. However, the limited findings on genetics available nowadays in the terms of this pathology indicated the need of more investigations with s special focus on genetics. Only with specific focus on pharmacogenetic relevant genetic variants of transcription factors it would become possible to uncover disease-associated SNPs and develop genetically-driven diagnostic and prognostic approaches.

  1. Ripke S, Neale BM, Corvin A, Walters JT, Farh KH, et al. (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511: 421-427. Link: https://goo.gl/SV6uLR
  2. Harrison PJ (2015) Recent genetic findings in schizophrenia and their therapeutic relevance. J Psychopharmacol 29: 85-96. Link: https://goo.gl/wSp0ks
  3. Gejman PV, Sanders AR, Kendler KS (2011) Genetics of schizophrenia: new findings and challenges. Annu Rev Genomics Hum Genet 12: 121-144. Link: https://goo.gl/IssdM0
  4. Johnson RD, Oliver PL, Davies KE (2008) SNARE proteins and schizophrenia: Linking synaptic and neurodevelopmental hypotheses. Acta Biochim Pol 55: 619-628. Link: https://goo.gl/hibxKf
  5. Watkins CC, Andrews SR (2016) Clinical studies of neuroinflammatory mechanisms in schizophrenia. Schizophr Res 176: 14-22. Link: https://goo.gl/ePNaXD
  6. Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF. (2006) Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res 81: 47-63. Link: https://goo.gl/C3rsTp
  7. Cooper GM (2000) Regulation of Transcription in Eukaryotes. The Cell: A Molecular Approach, 2nd edition. Sunderland (MA), Sinauer Associates. Link: https://goo.gl/uVem11
  8. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337: 1190-1195. Link: https://goo.gl/cCZNDj
  9. Quednow BB, Brzózka MM, Rossner MJ (2014) Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective. Cell Mol Life Sci 71: 2815-2835. Link: https://goo.gl/BhyRa7
  10. Guo AY, Sun J, Jia P, Zhao Z (2010) A novel microRNA and transcription factor mediated regulatory network in schizophrenia. BMC Syst Biol 4: 10. Link: https://goo.gl/hhYqOU
  11. Xu Y, Yue W, Yao Shugart Y, Li S, Cai L, et al. (2016) Exploring transcription factors-micrornas co-regulation networks in schizophrenia. Schizophr Bull 42: 1037-1045. Link: https://goo.gl/ghYasp
  12. Liou YJ, Wang HH, Lee MT, Wang SC, Chiang HL, et al. (2012) Genome-wide association study of treatment refractory schizophrenia in Han Chinese. PLoS ONE 7: e33598. Link: https://goo.gl/U560NH
  13. Massari ME, Murre C (2000) Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 20: 429-440. Link: https://goo.gl/sjEpws
  14. Quednow BB1, Brzózka MM, Rossner MJ. (2014) Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective. Cell Mol Life Sci 71(15): 2815-2835. Link: https://goo.gl/Xhydeo
  15. Hui L, Rao WW, Yu Q, Kou C, Wu JQ, et al. (2015) TCF4 gene polymorphism is associated with cognition in patients with schizophrenia and healthy controls. J Psychiatr Res 69: 95-101. Link: https://goo.gl/6WA3pR
  16. Zhu X, Gu H, Liu Z, Xu Z, Chen X, et al. (2013) Associations between TCF4 gene polymorphism and cognitive functions in schizophrenia patients and healthy controls. Neuropsychopharmacology 38: 683-689. Link: https://goo.gl/0D65sX
  17. Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, et al. (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473: 221-225. Link: https://goo.gl/bkpJjD
  18. Lennertz L, Quednow BB, Benninghoff J, Wagner M, Maier W, et al. (2011) Impact of TCF4 on the genetics of schizophrenia. Eur Arch Psychiatry Clin Neurosci 261 Suppl 2: S161-S165. Link: https://goo.gl/nsS29P
  19. Li S, Miao T, Sebastian M, Bhullar P, Ghaffari E, et al. (2012) The transcription factors Egr2 and Egr3 are essential for the control of inflammation and antigen-induced proliferation of B and T cells. Immunity 37: 685-696. Link: https://goo.gl/acpx8L
  20. Nishimura Y1, Takizawa R, Koike S, Kinoshita A, Satomura Y, et al. (2013) Association of decreased prefrontal hemodynamic response during a verbal fluency task with EGR3 gene polymorphism in patients with schizophrenia and in healthy individuals. Neuroimage 85: 527-534. Link: https://goo.gl/8KUm4z
  21. Gallitano-Mendel A, Izumi Y, Tokuda K, Zorumski CF, Howell MP, et al. (2007) The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty. Neuroscience 148: 633-643. Link: https://goo.gl/4PYBcU
  22. Yamada K, Gerber DJ, Iwayama Y, Ohnishi T, Ohba H, et al. (2007) Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc Natl Acad Sci USA 104: 2815-2820. Link: https://goo.gl/6xJqUU
  23. Kim SH, Song JY, Joo EJ, Lee KY, Ahn YM, et al. (2010) EGR3 as a potential susceptibility gene for schizophrenia in Korea. Am J Med Genet B Neuropsychiatr Genet 153B: 1355-1360. Link: https://goo.gl/33wbhZ
  24. Zhang R, Lu S, Meng L, Min Z, Tian J, et al. (2012) Genetic evidence for the association between the early growth response 3 (EGR3) gene and schizophrenia. PloS One 7: e30237. Link:© https://goo.gl/Dt6hof
  25. Huentelman MJ, Muppana L, Corneveaux JJ, Dinu V, Pruzin JJ, et al. (2015) Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk. PLoS One 10: e0135076. Link: https://goo.gl/kclfyA
  26. Williams AA, Ingram WM, Levine S, Resnik J, Kamel CM, et al. (2012) Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine. Neuropsychopharmacology 37: 2285-2298. Link: https://goo.gl/rw1yaD
  27. Malt EA, Juhasz K, Malt UF, Naumann T (2016) A role for the transcription factor Nk2 Homeobox 1 in schizophrenia: convergent evidence from animal and human studies. Front Behav Neurosci 10: 59. Link: https://goo.gl/avy19m
  28. Magno L, Kretz O, Bert B, Ersözlü S, Vogt J, et al. (2011) The integrity of cholinergic basal forebrain neurons depends on expression of Nkx2-1. Eur J Neurosci 34: 1767-1782. Link: https://goo.gl/ddWZtj
  29. Wiltschko AB, Pettibone JR, Berke JD (2010) Opposite effects of stimulant and antipsychotic drugs on striatal fast-spiking interneurons. Neuropsychopharmacology 35: 1261-1270. Link: https://goo.gl/lgx6Tq
  30. Marrone MC, Marinelli S, Biamonte F, Keller F, Sgobio CA, et al. (2006) Altered cortico-striatal synaptic plasticity and related behavioural impairments in reeler mice. Eur J Neurosci 24: 2061-2070. Link: https://goo.gl/1ai2Pj
  31. Ammassari-Teule M, Sgobio C, Biamonte F, Marrone C, Mercuri NB, et al. (2009) Reelin haploinsufficiency reduces the density of PV+ neurons in circumscribed regions of the striatum and selectively alters striatal-based behaviors. Psychopharmacology (Berl) 204: 511-521. Link: https://goo.gl/SFn4Ln
  32. Peall KJ, Kurian MA (2015) Benign hereditary chorea: an update. Tremor Other Hyperkinet Mov (NY) 5: 314. Link: https://goo.gl/MAaH3y
  33. Nielsen JA, Berndt JA, Hudson LD, Armstrong RC (2004) Myelin transcription factor 1 (Myt1) modulates the proliferation and differentiation of oligodendrocyte lineage cells. Mol Cell Neurosci 25: 111-123. Link: https://goo.gl/Bn34Z1
  34. Romm E, Nielsen JA, Kim JG, Hudson LD (2005) Myt1 family recruits histone deacetylase to regulate neural transcription. J Neurochem 93: 1444-1453. Link: https://goo.gl/cpAJTN
  35. Vrijenhoek T, Buizer-Voskamp JE, van der Stel I, Strengman E, Genetic Risk and Outcome in Psychosis (GROUP) Consortium, et al. (2008) Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am J Hum Genet 83: 504-510. Link: https://goo.gl/13VMXG
  36. Li W, Wang X, Zhao J, Lin J, Song XQ, et al. (2012) Association study of myelin transcription factor 1-like polymorphisms with schizophrenia in Han Chinese population. Genes Brain Behav 11: 87-93. Link: https://goo.gl/rTAMjj
  37. Fleischmann А, Hvalby O, Jensen V, Strekalova T, Zacher C, et al. (2003) Impaired longterm memory and NR2Atype NMDA receptordependent synaptic plasticity in mice lacking cFos in the CNS. J Neurosci 23: 9116-9122. Link: https://goo.gl/aAp0Mn
  38. Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH (2007) NMDA receptors and schizophrenia. Curr Opin Pharmacol 7: 48-55. Link: https://goo.gl/nshKFM
  39. Vanhoutte P, Barnier JV, Guibert B, Pagès C, Besson MJ, et al. (1999) Glutamate induces phosphorylation of Elk1 and CREB, along with cfos activation, via an extracellular signalregu lated kinasedependent pathway in brain slices. Mol Cell Biol 19: 136-146. Link: https://goo.gl/SrqE6a
  40. Bartzokis G (2002) Schizophrenia: Breakdown in the wellregulated lifelong process of brain development and maturation. Neuropsychopharmacology 27: 672-683. Link: https://goo.gl/4pXL45
  41. Fatemi SH, Folsom TD (2009) The neurodevelop mental hypothesis of schizophrenia, revisited. Schizophr Bull 35: 528-548. Link: https://goo.gl/VOxBxy
  42. Torkamani A, De B, Thomas EA (2010) Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. Genome Res 20: 403-412. Link: https://goo.gl/BnePWN
  43. Zhao A, Li M (2012) Neuroanatomical substrates of the disruptive effect of olanzapine on rat maternal behavior as revealed by cFos immunoreactivity. Pharmacol Biochem Behav 103: 174-180. Link: https://goo.gl/10JOeg
  44. Zamberletti E, Viganò D, Guidali C, Rubino T, Parolaro D. (2012) Long lasting recovery of psychotic like symptoms in isolationreared rats after chronic but not acute treatment with the cannabinoid antagonist AM251. Int J Neuro psycho pharmacol 15: 267-280. Link: https://goo.gl/vYlC0D
  45. Brady AM, Saul RD, Wiest MK (2010) Selective deficits in spatial working memory in the neonatal ven tral hippocampal lesion rat model of schizophrenia. Neuropharmacology 59: 605-611. Link: https://goo.gl/svhGKE
  46. Glover JNM, Harrison SC (1995) Crystal structure of the heterodimericb ZIP transcription factor cFos–c Jun bound to DNA. Nature 373: 257-261. Link: https://goo.gl/RWw0V5
  47. Alberini CM (2009) Transcription factors in longterm memory and synaptic plasticity. Physiol Rev 89: 121-145. Link: https://goo.gl/LNQ7bm
  48. Sanyal S, Sandstrom DJ, Hoeffer CA, Ramaswam M (2002) AP1 functions upstream of CREB to control synaptic plasticity in Drosophila. Nature 416: 870-874. Link: https://goo.gl/cJiXD9
  49. Glyvuk N, Tsytsyura Y, Geumann C, D'Hooge R, Hüve J, et al. (2010) AP1/ sigma1Badaptin mediates endosomal synaptic vesicle recycling, learning and memory. EMBO J 29: 1318-1330. Link: https://goo.gl/lalTYr
  50. Boyajyan AS, Atshemyan SA, Zakharyan RV (2015) [Association of schizophrenia with variations in genes encoding transcription factors]. Mol Biol (Mosk) 49: 977-983. Link: https://goo.gl/jm8qQw
© 2016 Zakharyan R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.