Deneysel şizofreni modellerinin oluşturulması ve deneysel yöntemlerle şizofreni belirtilerinin değerlendirilmesi

Yaygın ve ciddi bir psikiyatrik hastalık olan şizofreni, dünya nüfusunun %0.5-%1’ini etkilemektedir. Şizofreni çeşitli semptomlarla seyretmesi nedeniyle kompleks klinik bulguları olan nörogelişimsel bir bozukluktur. Etiyolojisi tam olarak bilinemeyen şizofrenin gelişiminde beyindeki kimyasalların, yapısal farklılıkların ve genlerin etkisi olduğu düşünülürken; patogenezinde çevresel, psikolojik ve sosyal etkenlerin rolü olduğu düşünülmektedir. Deneysel hayvan modellerinin geliştirilmesi, insanlarda modellenemeyen bu hastalığın fizyopatolojisini ve nörobiyolojik temellerinin anlaşılmasına imkân sağlamaktadır. Deneysel yöntem olarak kalsineurin, neuregulin gibi genler genetik modellerde; prenatal stres gelişimsel modellerde; dopaminerjik agonist gibi ilaçlar ilaç ve kimyasal modellerde; hipokampal lezyon neonatal hipokampüs lezyon modellerinde deneysel hayvan modelleri oluşturulmasında kullanılmaktadır. Düşük enerji, motivasyon eksikliği, delüzyon, halüsinasyon, anlamada ve öğrenmede yetersizlik, bellekte zayıflama vb. şizofreninin bilinen semptomlarındandır. Değişik yöntemlerle oluşturulan deneysel hayvan modellerinde hangi semptomun ortaya çıktığını belirlemek için davranışsal test yöntemleri kullanılmaktadır. Bu test yöntemlerinden prepulse inhibisyon ve yeni obje tanıma testleri çoğunlukla kullanılmaktadır. Yeni obje tanıma testi şizofreninin kognitif semptomlarıyla, prepulse inhibisyon testi ise pozitif semptomlarıyla ilgilidir. Genetik, gelişimsel ve kimyasal modellerle oluşturulan bu hastalığın temellerini kavrayabilmek ve yeni tedaviler geliştirebilmek için deney hayvanı modellerinin geliştirilmesi ve daha geniş çaplı çalışmalarda kullanılması gerektiği sonucuna varılmıştır.

Anahtar Kelimeler:

Bellek, deneysel hayvan modelleri, fizyopatoloji, genetik, şizofreni

Development of experimental schizophrenia models and evaluation of schizophrenia symptoms with tests

Schizophrenia, a common and serious psychiatric disorder, affects 0.5% to 1% of the world population. Schizophrenia is a neurodevelopmental disorder with complex clinical findings due to various symptoms. While the etiology of schizophrenia is unknown, it is thought that chemicals in the brain, structural differences and genes have effects on the disease; environmental, psychological and social factors are thought to play a role in the pathogenesis. The development of experimental animal models allows for better understanding of the physiopathology and neurobiological bases of this disease which cannot be modeled in humans. As different experimental methods, genes such as calcineurin and neuregulin in genetic models; prenatal stress in developmental models; drugs such as dopaminergic agonist in pharmaceutical and chemical models; hippocampal lesion is used in the production of experimental animal models. Low energy, lack of motivation, delusion, hallucinations, inability to understand and learning, memory attenuation etc. are known as symptoms of schizophrenia. In experimental animal models produced by different methods, behavioral test models are used to determine which symptoms occur. Among these test methods, prepulse inhibition and new object recognition tests are mostly used. The new object recognition test is related to the cognitive symptoms of schizophrenia while the prepulse inhibition test is related to its positive symptoms. In order to understand the basics of this disease, which is formed by genetic, developmental and chemical models, and to develop new treatments, we reached a conclusion that more advanced experimental animal models should be developed and used in more comprehensive studies.

Keywords:

Memory, experimental animal models, physiopathology, genetic, schizophrenia,

PDF

___

Tamminga CA, Holcomb HH. Phenotype of schizophrenia: a review and formulation. Mol Psychiatry 2005;10:27–39.
Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron 2006;1:139-153.
World Health Organization Schizophrenia 2016.
Göktalay G., Aktaş Ö., Kayır H. Turkiye Klinikleri J Pharmacol-Special Topics. 2016;4(1):53-60.
Hay A, Byers A, Sereno M, Basra MK, Dutta S. Asenapine versus placebo for schizophrenia. Cochrane Database Syst Rev. 2015 Nov 24;(11):CD011458.
Perry W, Geyer MA, Braff DL: Sensorimotor gating and thought disturbance measured in close temporal proximity in schizophrenic patients. Arch Gen Psychiatry. 1999;56:277-281.
Ural C, Öncü F, Belli H, Soysal H. Adli psikiyatrik süreç içindeki şizofreni hastalarının şiddet davranışı değişkenleri: bir olgu kontrol çalışması. Türk Psikiyatri Dergisi. 2013;24:17-24.
Mouri A, Nagai T, Ibi D, Yamada K. Animal models of schizophrenia for molecular and pharmacological intervention and potential candidate molecules. Neurobiol Dis.2013;53:61-74.
Farrell MS, Werge T, Sklar P, Owen MJ, Ophoff RA, O’Donovan MC, Corvin A, Cichon S, Sullivan PF. Evaluating historical candidate genes for schizophrenia. Mol Psychiatry. 2015;1-8.
Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008;13(1):36-64.
Merelo V, Durand D, Lescallette AR, Vrana KE, Hong LE, Faghihi MA, Bellon A. Associating schizophrenia, long non-coding RNAs and neurostructural dynamics. Front Mol Neurosci. 2015;8:57.
Ahmed AO, Mantini AM, Fridberg DJ, Buckley PF. Brain-derived neurotrophic factor (BDNF) and neurocognitive deficits in people with schizophrenia: a meta-analysis. Psychiatry Res. 2015;226(1):1-13.
Negron‑Oyarzo et al. Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior. Biol Res. 2016;49:16.
Le Strat Y, Ramoz N, Gorwood P. The role of genes involved in neuroplasticity and neurogenesis in the observation of a gene-environment interaction (GxE) in schizophrenia. Current Molecular Medicine. 2009;4:506-518.
Williams N, O’Donovan M, Owen M. Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? Schizophr Bull. 2005;31:800-805.
Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ, et al. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. The Journal of clinical investigation. 2004;113:1353-1363.
Weickert CS, Rothmond DA, Hyde TM, Kleinman JE, Straub RE. Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophrenia research. 2008;98:105-110.
Weickert CS, Straub RE, McClintock BW, Matsumoto M, Hashimoto R, Hyde TM, et al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Archives of general psychiatry. 2004;61:544-555.
Tang J, LeGros RP, Louneva N, Yeh L, Cohen JW, Hahn CG, et al. Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Human molecular genetics. 2009;18:3851-3863.
Rusnak F, Mertz P. Calcineurin: form and function. Physiol Rev. 2000;80:1483-1521.
Groth RD, Dunbar RL, Mermelstein PG. Calcineurin regulation of neuronal plasticity. Biochem Biophys Res Commun. 2003;311:1159-1171.
Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci USA. 2003;100(15):8987-8992.
Horiuchi Y, Ishiguro H, Koga M, Inada T, Iwata N, Ozaki N, Ujike H, Muratake T, Someya T, Arinami T. Support for association of the PPP3CC gene with schizophrenia. Mol Psychiatry. 2007;12(10):891-893.
Stefansson H, Steinthorsdottir V, Thorgeirsson TE, Gulcher JR, Stefansson K. Neuregulin 1 and schizophrenia. Ann Med. 2004;36(1):62-71.
Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006;32(2): 200-202.
Dong E, Dzitoyeva SG, Matrisciano F, Tueting P, Grayson DR, Guidotti A. Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice. Biol Psychiatry. 2015;77:589-596.
Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006;26:365-384.
Bennet S and Gronier B. Modulation of striatal dopamine release in vitro by agonists of the glycine B site of NMDA receptors; interaction with antipsychotics. Eur J Pharmacol. 2005;527:52-59.
Scarr E, Beneyto M, Meador-Woodruff JH and Dean B: Cortical glutamatergic markers in schizophrenia. Neuropsychopharmacology. 2005;30:1521-1531.
Rubeša G, Gudelj L, Kubinska N. Etiology of schizophrenia and therapeutic options. Psychiatr Danub. 2011;23(3):308-315.
Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R. Study of a new schizophrenomimetic drug; sernyl. AMA Arch Neurol Psychiatry. 1959;81:363-369.
Garey RE. PCP (phencyclidine): an update. J Psychedelic Drugs. 1979;11:265-275.
Mansbach RS, Geyer MA. Parametric determinants in prestimulus modification of acoustic startle: interaction with ketamine. Psychopharmacology (Berl). 1991;105:162-168.
Carlsson M, Carlsson A. Schizophrenia: a subcortical neurotransmitter imbalance syndrome? Schizophr Bull 1990;16(3):425-432.
Robinson TE, Becker JB. Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res. 1986;396(2):157-198.
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl). 2001 Jul;156(2-3):117-154.
Geyer MA, Braff DL, Swerdlow NR. Startle-response measures of information processing in animals: relevance to schizophrenia. In: Haug M, Whalen RE, eds. Animal models of human emotion and cognition. Washington, DC: APA Books. 1999:103–116.
Swerdlow NR, Geyer MA. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr Bull.1998;24:285-301.
Uzbay T. Şizofreni tedavisinde yeni farmakolojik yaklaşımlar. Turk Psikiyatri Derg. 2009;20:175-182.
Uslu G, Savci V, Buyukuysal LR, Goktalay G. CDP-choline attenuates scopolamine induced disruption of prepulse inhibition in rats: involvement of central nicotinic mechanism. Neurosci Lett. 2014;569:153-157.
Sams-Dodd F, Lipska BK, Weinberger DR. Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood. Psychopharmacology (Berl). 1997;132(3):303-310.
Braff DL, Geyer MA, Swerdlow NR. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl).2001;156:234-258.
Geyer MA, Braff DL. Startle habituation and sensorimotor gating in schizophrenia and related animal models. Schizophr Bull. 1987;13:643-668.
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology. 2001;156:117-154.
Braff DL, Geyer MA. Sensorimotor gating and schizophrenia: human and animal model studies. Arch Gen Psychiatry. 1990;47:181-188.
Uzbay T. Şizofreni tedavisinde yeni bir hedef agmatin ve poliamin sistemi: Derleme. Klinik Psikiyatri. 2009;12:188-196.
Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L. Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology. 1978;15:339-343.
Swerdlow NR, Paulsen J, Braff DL, Butters N, Geyer MA, Swenson MR. Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington's disease. J Neurol Neurosurg Psychiatry. 1995;58:192-200.
Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL,Hallet M. Sensorimotor gating in boys with Tourette's syndrome and ADHD:preliminary results. Biol Psychiatry.1996;39:33-41.
Swerdlow NR, Benbow CH, Zisook S, Geyer MA, Braff DL. Apreliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder. Biol Psychiatry. 1993;33:298-301.
Uzbay T. Şizofreni Tedavisinde Yeni Farmakolojik Yaklaşımlar. Türk Psikiyatri Dergisi. 2009; 20(2):175-182.
Anokhin AP, Heath AC, Myers E ve ark. Genetic influences on prepulse inhibition of startle reflex in humans. Neurosci Lett. 2003; 353:45-48.
Li, S.J.,Huang,Z.Y.,Ye,Y.L.,Yu,Y.P.,Zhang,W.P.,Wei,E.Q., Zhang, Q.Influence of object material and inter-trial interval on novel object recognition test in mice. Zhejiang da xue xue bao Yi xue Ban.J. Zhejiang Univ. Med. Sci. 2014;43,346-352.
Sutcliffe JS, Marshall KM, Neill JC. Influence of gender on working and spatial memory in the novel object recognition task in the rat. Behav Brain Res. 2007;177:117-125.
Pellow S, File SE. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav. 1986; 24(3):525-529.
Kinnavane L, Amin E, Olarte-Sánchez CM, Aggleton JP. Detecting and discriminating novel objects: The impact of perirhinal cortex disconnection on hippocampal activity patterns. Hippocampus. 2016;26(11):1393-1413.
Barnett SA. The rat: a study in behavior. New Jersey: Transaction Publishers, 2007.
Foa EB, Keane TM, Freidman MJ, Kohen JA, (editors). Effective Treatments for PTSD: Practice Guidelines From the International Society of Traumatic Stress Studies. New York: Guilford Press, 2005.
Boissier JR, Simon P, Soubrie P, Airaksinen M, (editors). New approaches to the study of anxiety and anxiolytic drugs in animal: CNS and behavioral pharmacology. New York: Pergamon, 1976.
Nikiforuk A, Kos T, Hołuj M, Potasiewicz A, Popik P. Positive allosteric modulators of alpha7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats. Neuropharmacology. 2016;101:389-400.
Albani SH, McHail DG, Dumas TC. Developmental studies of the hippocampus and hippocampal-dependent behaviors: insights from interdisciplinary studies and tips for new investigators. Neurosci Biobehav Rev. 2014;43:183-190.
Watson DJ, King MV, Gyertyán I, Kiss B, Adham N, Fone KC. The dopamine D₃-preferring D₂/D₃ dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia. Eur Neuropsychopharmacol. 2016; 26(2):208-224.