psychiatryПСИХИАТРИЯPsychiatry (Moscow) (Psikhiatriya)1683-83192618-6667FSBSI “The Mental Health Research Centre”; LLC «Publisher «MIA»10.30629/2618-6667-2018-77-16-25psychiatry-312Research ArticleВОПРОСЫ КЛИНИЧЕСКОЙ И БИОЛОГИЧЕСКОЙ ПСИХИАТРИИФерменты глутаматного обмена в лобной, лимбической коре и мозжечке: аномалии при шизофренииGlutamate metabolizing enzymes in frontal, cingulate and cerebellar cortex: anomalities revealed in schizophreniaСавушкинаОльга КонстантиновнаSavushkinaOlga

ведущий научный сотрудник, кандидат биологических наук

PhD in biology, leading researcher

neurochem06@mail.ruБокшаИрина СергеевнаBokshaIrina

главный научный сотрудник, доктор биологических наук, старший научный сотрудник

PhD in biology, doctor of natural sciences, chief researcher

neurochem06@mail.ruТерешкинаЕлена БорисовнаTereshkinaElena

старший научный сотрудник, кандидат биологических наук

PhD in biology, senior researcher

neurochem06@mail.ruПрохороваТатьяна АндреевнаProkhorovaTatyana

научный сотрудник

researcher

gnidra@mail.ruВоробьеваЕлена АнатольевнаVorobyevaElena

научный сотрудник, кандидат биологических наук

PhD in biology, researche

vaa-vea@yandex.ruБурбаеваГульнур ШингожиевнаBurbaevaGulnur

доктор биологических наук, заведующая лабораторией нейрохимии, профессор

PhD in biology, doctor of natural sciences, professor

gburb@mail.ruФГБНУ «Научный центр психического здоровья», МоскваРоссияFSBSI «Mental Health Research Centre», MoscowRussian Federation2018311020181771625Copyright © Савушкина О.К., Бокша И.С., Терешкина Е.Б., Прохорова Т.А., Воробьева Е.А., Бурбаева Г.Ш., 20182018Савушкина О.К., Бокша И.С., Терешкина Е.Б., Прохорова Т.А., Воробьева Е.А., Бурбаева Г.Ш.Savushkina O., Boksha I., Tereshkina E., Prokhorova T., Vorobyeva E., Burbaeva G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.journalpsychiatry.com/jour/article/view/312

Цель исследования: сравнение распределения активности глутаминсинтетазы (ГС), глутаматдегидрогеназы (ГДГ) и количества их иммунореактивных форм в лобной, передней и задней лимбической коре и коре мозжечка больных шизофренией и в контрольной группе. Материал и методы исследования: группа больных шизофренией: четыре мужчины и четыре женщины (36–80 лет) с диагнозами (по МКБ-10) по три пациента — F20.00 и F20.02, по одному — F20.31 и F20.50. Контрольная группа: восемь мужчин и одна женщина (29–79 лет). Группы достоверно не различались по возрасту, постмортальному интервалу (p > 0,05). Применены методы непараметрической статистики. Результаты: в ферментативной активности ГС в исследованных структурах мозга достоверных межгрупповых различий не наблюдалось. Уровень иммунореактивной ГС у больных шизофренией по сравнению с контролем в лобной коре понижен (U-тест Манна–Уитни, р < 0,001), в передней лимбической коре не изменен, а в задней лимбической коре (р < 0,001) и мозжечке повышен (р < 0,004). Уровень иммунореактивного белка, подобного ГС (ГСПБ), повышен во всех четырех областях мозга (р < 0,04). Ферментативная активность ГДГ при шизофрении по сравнению с контролем достоверно повышена в лобной коре (p < 0,004), задней лимбической коре (p < 0,05) и мозжечке (p < 0,002) и не изменена в передней лимбической коре. У больных шизофренией по сравнению с контролем установлено: в лобной коре повышение уровня иммунореактивных ГДГI, ГДГII и ГДГIII (р < 0,01); в задней лимбической коре повышение уровня иммунореактивных форм ГДГI, ГДГII и ГДГIII (р < 0,02); в мозжечке — увеличение уровня иммунореактивных форм ГДГII и ГДГIII (р < 0,02 и р < 0,001 соответственно). Заключение: изменение уровней ГС, ГСПБ и изоформ ГДГ в мозге больных шизофренией служит одной из причин нарушения глутаматного метаболизма в исследованных структурах мозга и может считаться важным аспектом патогенеза шизофрении.

Aim: to compare distributions of glutamine synthetase (GS) and glutamate dehydrogenase (GDH) activities and amounts of their immunoreactive forms amongst frontal, anterior, posterior cingulate, and cerebellar cortices in schizophrenia cases and controls. Material and methods: group of patients with schizophrenia: 4 men and 4 women (36–80 years old) diagnosed according ICD-10 (F20.00, F20.02, F20.31, and F20.50 — 3, 3, 1 and 1 patient). Control group: 8 men and 1 woman (29–79 years old). No significant between-group differences were found in age and postmortem interval (p > 0,05). Non-parametric statistics was used. Results: no signifcant between-group difference was observed in GS activity in investigated brain structures (p > 0,05). Following differences were found in schizophrenia compared with controls: amount of immunoreactive GS was decreased in frontal cortex (p < 0,001), it was increased in posterior cingulate cortex and cerebellum (p < 0,001 and p < 0,004), but unchanged in anterior cingulate cortex, whereas level of GS-like protein (GSLP) was signifcantly elevated in all four brain structures (р < 0,004, р < 0,02, р < 0,04, and р < 0,001). When compared with controls, schizophrenia cases displayed elevated GDH activity in frontal, posterior cingulate cortex and cerebellum (p < 0,004, p < 0,05, and p < 0,002), but unchanged in anterior cingulate cortex. When compared with control, following differences were found in schizophrenia: elevation in levels of immunoreactive GDHI, GDHII, and GDHIII in frontal cortex (р < 0,008, р < 0,003, and р < 0,001); elevation in levels of immunoreactive GDHI, GDHII, and GDHIII in posterior cingulate cortex (р < 0,004, р < 0,001, and р < 0,02); elevation in levels of immunoreactive GDHII and GDHIII in cerebellum (р < 0,02 and р < 0,001). No between-group differences in levels of immunoreactive GDH forms were found in anterior cingulate cortex. Conclusion: alteration in levels of GS, GSLP, and GDH forms in brain of patients with schizophrenia is one of causes of glutamate metabolism disturbances in these brain structures and an important aspect of schizophrenia pathogenesis.

глутаминсинтетазаглутаматдегидрогеназашизофрениямозг человекаECL-иммуноблоттингglutamine synthetaseglutamate dehydrogenaseschizophreniahuman brainECL-immunoblottingReferencesGluck M.R., Thomas R.G., Davis K.L. et al. Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients. Am. J. Psychiatry. 2002;59:1165–1173. doi: 10.1176/appi.ajp.159.7.1165Gluck M.R., Thomas R.G., Davis K.L. et al. Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients. Am. J. Psychiatry. 2002;159:1165– 1173. doi: 10.1176/appi.ajp.159.7.1165Hu W., MacDonald M.L., Elswick D.E., Sweet R.A. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann. NY Acad. Sci. 2015;1338:38–57. doi: 10.1111/nyas.12547Hu W., MacDonald M.L., Elswick D.E., Sweet R.A. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann. NY Acad. Sci. 2015;1338:38–57. doi: 10.1111/nyas.12547Mouchlianitis E., Bloomfield M.A., Law V., Beck K., Selvaraj S., Rasquinha N., Waldman A., Turkheimer F.E., Egerton A., Stone J., Howes O.D. Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive. Schizophr. Bull. 2016;42(3):744–752. doi: 10.1093/schbul/sbv151Mouchlianitis E., Bloomfield M.A., Law V., Beck K., Selvaraj S., Rasquinha N., Waldman A., Turkheimer F.E., Egerton A., Stone J., Howes O.D. Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-respon-sive. Schizophr. Bull. 2016;42(3):744–752. doi: 10.1093/schbul/sbv151Funk A.J., Rumbaugh G., Harotunian V., McCullumsmith R.E., Meador-Woodruff J.H. Decreased expression of NMDA receptor-associated proteins in frontal cortex of elderly patients with schizophrenia. Neuroreport. 2009;20(11):1019–1022. http://doi.org/10.1097/ WNR.0b013e32832d30d9Funk A.J., Rumbaugh G., Harotunian V., McCullumsmith R.E., Meador-Woodruff J.H. Decreased expression of NMDA receptor-associated proteins in frontal cortex of elderly patients with schizophrenia. Neuroreport. 2009;20(11):1019–1022. http://doi.org/10.1097/ WNR.0b013e32832d30d9Derouiche A., Frotscher M. Astroglial processes around identified glutamatergic synapses contain glutamine synthetase, evidence for transmitter degradation. Brain Res. 1991;552(2):346–350.Derouiche A., Frotscher M. Astroglial processes around identified glutamatergic synapses contain glutamine synthetase, evidence for transmitter degradation. Brain Res. 1991;552(2):346–350.Boksha I.S., Tereshkina E.B., Burbaeva G.Sh. Glutamine synthetase and glutamine synthetase-like protein from human brain, purification and comparative characterization. J. Neurochem. 2000;75:2574– 2582.Boksha I.S., Tereshkina E.B., Burbaeva G.Sh. Glutamine synthetase and glutamine synthetase-like protein from human brain, purification and comparative characterization. J. Neurochem. 2000;75:2574– 2582.Shimizu E., Shirasawa H., Kodama K., Kuroyanagi H., Shirasawa T., Sato T., Simizu B. Glutamate dehydrogenase mRNA is immediately induced after phencyclidine treatment in the rat brain. Schizophr. Res. 1997;25(3):251–258.Shimizu E., Shirasawa H., Kodama K., Kuroyanagi H., Shirasawa T., Sato T., Simizu B. Glutamate dehydrogenase mRNA is immediately induced after phencyclidine treatment in the rat brain. Schizophr. Res. 1997;25(3):251–258.Smesny S., Gussew A., Biesel N.J., Schack S., Walther M., Rzanny R., Milleit B., Gaser C., Sobanski T., Schultz C.C., Amminger P., Hipler U.C., Sauer H., Reichenbach J.R. Glutamatergic dysfunction linked to energy and membrane lipid metabolism in frontal and anterior cingulate cortices of never treated first-episode schizophrenia patients. Schizophr. Res. 2015;168(1–2):322–329. http://doi.org/10.1016/j.schres.2015.07.013Smesny S., Gussew A., Biesel N.J., Schack S., Walther M., Rzanny R., Milleit B., Gaser C., Sobanski T., Schultz C.C., Amminger P., Hipler U.C., Sauer H., Reichenbach J.R. Glutamatergic dysfunction linked to energy and membrane lipid metabolism in frontal and anterior cingulate cortices of never treated first-episode schizophrenia patients. Schizophr. Res. 2015;168(1–2):322–329. http://doi. org/10.1016/j.schres.2015.07.013Reid M.A., Stoeckel L.E., White D.M., Avsar K.B., Bolding M.S., Akella N.S., Knowlton R.C., den Hollander J.A., Lahti A.C. Assessments of function and biochemistry of the anterior cingulate cortex in schizophrenia. Biol. Psychiatry. 2010;68(7):625–633. doi: 10.1016/j.biopsych.2010.04.013Reid M.A., Stoeckel L.E., White D.M., Avsar K.B., Bolding M.S., Akella N.S., Knowlton R.C., den Hollander J.A., Lahti A.C. Assessments of function and biochemistry of the anterior cingulate cortex in schizophrenia. Biol. Psychiatry. 2010;68(7):625–633. doi: 10.1016/j. biopsych.2010.04.013Mitelman S.A., Shihabuddin L., Brickman A.M., Hazlett E.A., Buchsbaum M.S. Volume of the cingulate and outcome in schizophrenia. Schizophr. Res. 2005;72(2–3):91–108.Mitelman S.A., Shihabuddin L., Brickman A.M., Hazlett E.A., Buchsbaum M.S. Volume of the cingulate and outcome in schizophrenia. Schizophr. Res. 2005;72(2–3):91–108.Востриков В.М., Артюхова О.А., Холмова М.А., Самородов А.В., Уранова Н.А. Пространственная организация олигодендроцитов и пирамидных нейронов в передней лимбической коре в норме и при шизофрении (новые возможности компьютерной морфометрии). Журнал неврологии и психиатрии им. С.С. Корсакова. 2013;113(12):67–70.Vostrikov V.M., Artiukhova O.A., Kholmova M.A., Samorodov A.V., Uranova N.A. The spatial organization of oligodendrocytes and pyramidal neurons in the frontal limbic cortex of patients with schizophrenia and healthy people: a computer morphometric study. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2013;113(12):67–70. (In Russ.).Roberts R.S., Barksdale K.A., Roche J.K., Lanti A.C. Decreased synaptic and mitochondrial density in the postmortem anterior cingulated cortex in schizophrenia. Schizophr. Res. 2015;168(1–2):543–553. https://doi.org/10.1016/j.schres.2015.07.016/Roberts R.S., Barksdale K.A., Roche J.K., Lanti A.C. Decreased syn- aptic and mitochondrial density in the postmortem anterior cingulated cortex in schizophrenia. Schizophr. Res. 2015;168(1–2):543–553. https://doi.org/10.1016/j.schres.2015.07.016/Nelson B.D., Bjorkquist O.A., Olsen E.K., Herbener E.S. Schizophrenia symptom and functional correlates of anterior cingulate cortex activation to emotion stimuli: An fMRI investigation. Psychiatry Research — Neuroimaging. 2015;234(3):285–291. doi: 10.1016/j.pscychresns.2015.11.001Nelson B.D., Bjorkquist O.A., Olsen E.K., Herbener E.S. Schizophrenia symptom and functional correlates of anterior cingulate cortex activation to emotion stimuli: An fMRI investigation. Psychiatry Research — Neuroimaging. 2015;234(3):285-291. doi: 10.1016/j.pscychresns.2015.11.001Egerton A., Brugger S., Raffin M., Barker G.J., Lythgoe D.J., McGuire P.K., Stone J.M. Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology. 2012;37(11):2515–2521. doi: 10.1038/ npp.2012.113Egerton A., Brugger S., Raffin M., Barker G.J., Lythgoe D.J., McGuire P.K., Stone J.M. Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology. 2012;37(11):2515–2521. doi: 10.1038/ npp.2012.113Diamond A. Close interrelation of motor development and cognitive development and of the cerebellum and prefrontal cortex. Child Dev. 2000;71(1):44–45.Diamond A. Close interrelation of motor development and cognitive development and of the cerebellum and prefrontal cortex. Child Dev. 2000;71(1):44–45.Bolbecker A.R., Petersen I.T., Kent J.S., Howell J.M., O’Donnell B.F., Hetrick W.P. New insights into the nature of cerebellar-dependent eyeblink conditioning deficits in schizophrenia: A hierarchical linear modeling approach. Front. Psychiatry. 2016;25(7):4. http://doi.org/10.3389/fpsyt.2016.00004Bolbecker A.R., Petersen I.T., Kent J.S., Howell J.M., O’Donnell B.F., Hetrick W.P. New insights into the nature of cerebellar-dependent eyeblink conditioning deficits in schizophrenia: A hierarchical linear modeling approach. Front. Psychiatry. 2016;25(7):4. http://doi.org/10.3389/fpsyt.2016.00004Miquel M., Vazquez-Sanroman D., Carbo-Gas M., Gil-Miravet I., Sanchis-Segura C., Carulli D., Manzo J., Coria-Avila G.A. Have we been ignoring the elephant in the room? Seven arguments for considering the cerebellum as part of addiction circuitry. Neurosci. Biobehav. Rev. 2016;60:1–11. doi: 10.1016/j.neubiorev.2015.11.005Miquel M., Vazquez-Sanroman D., Carbo-Gas M., Gil-Miravet I., Sanchis-Segura C., Carulli D., Manzo J., Coria-Avila G.A. Have we been ignoring the elephant in the room? Seven arguments for considering the cerebellum as part of addiction circuitry. Neurosci. Biobehav. Rev. 2016;60:1–11. doi: 10.1016/j.neubiorev.2015.11.005Rasser P.E., Schall U., Peck G., Cohen M., Johnston P., Khoo K., Carr V.J., Ward P.B., Thompson P.M. Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching. Neuroimage. 2010;53(4):1175–1180. http://doi.org/10.1016/j.neu-roimage.2010.07.018Rasser P.E., Schall U., Peck G., Cohen M., Johnston P., Khoo K., Carr V.J., Ward P.B., Thompson P.M. Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching. Neuroimage. 2010;53(4):1175–1180. http://doi.org/10.1016/j.neu- roimage.2010.07.018Iqbal K., Ottaway J.H. Glutamine synthetase in muscle and kidney. Biochem. 1970;119:145–156.Iqbal K., Ottaway J.H. Glutamine synthetase in muscle and kidney. Biochem. 1970;119:145–156.Fahien L.A., Wiggert B.O., Cohen P.P. Crystallization and kinetic properties of glutamate dehydrogenase from frog liver. J. Biol. Chem. 1965;240:1083–1090.Fahien L.A., Wiggert B.O., Cohen P.P. Crystallization and kinetic properties of glutamate dehydrogenase from frog liver. J. Biol. Chem. 1965;240:1083–1090.Терешкина Е.Б., Бокша И.С., Савушкина О.К., Бурбаева Г.Ш. Глутаминсинтетаза и белок, подобный глутаминсинтетазе, в лобной коре при шизофрении. Журнал неврологии и психиатрии им. С.С. Корсакова. 2000;100(7):51–53.Tereshkina E.B., Bokina I.S., Savushkina O.K., Burbaeva G.Sh. Glutamine synthetase and related protein in the frontal cortex in schizophrenia. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2000;100(7):51–53. (In Russ.).Boksha I.S., Savushkina O.K., Tereshkina E.B., Prokhorova T.A., Mukaetova-Ladinska E.B. Enzymes of glutamate system. In: Parrot S., Denoroy L. (eds.) Biochemical Approaches for Glutamatergic Neurotransmission. Neuromethods, vol. 130. New York, NY, Humana Press; 2018:469–506. doi: https://doi.org/10.1007/978-1-4939-7228-9_15Boksha I.S., Savushkina O.K., Tereshkina E.B., Prokhorova T.A., Mukaetova-Ladinska E.B. Enzymes of Glutamate System. In: Parrot S., Denoroy L. (eds.) Biochemical Approaches for Glutamatergic Neurotransmission. Neuromethods, vol 130. New York, NY, Humana Press; 2018:469–506. doi: https://doi.org/10.1007/978-1-4939-7228-9_15Burbaeva G.S., Boksha I.S., Tereshkina E.B., Savushkina O.K., Starodubtseva L.I., Turishcheva M.S., Mukaetova-Ladinska E. Systemic neurochemical alterations in schizophrenic brain, glutamate metabolism in focus. Neurochem. Res. 2007;32(9):1434–1444. doi.org/10.1007/ s11064-007-9328-7.Burbaeva G.S., Boksha I.S., Tereshkina E.B., Savushkina O.K., Starodubtseva L.I., Turishcheva M.S., Mukaetova-Ladinska E. Systemic neurochemical alterations in schizophrenic brain, glutamate metabolism in focus. Neurochem. Res. 2007;32(9):1434–1444. doi.org/10.1007/ s11064-007-9328-7.

The authors declare that there are no conflicts of interest present.