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İnsülinin Sinaptik Plastisitedeki Rolü: Uzun Dönemli Baskılanma

Year 2024, Volume: 46 Issue: 3, 455 - 462, 27.05.2024
https://doi.org/10.20515/otd.1400449

Abstract

Giriş: İnsülin, pankreatik beta hücrelerinden salgılanan glukoz homeostazisinin sürdürülmesinde gerekli bir hormondur. Periferik etkileri ayrıntılı bir şekilde açığa çıkarılmasına rağmen kognitif fonksiyonlar üzerine etkisi belirsizdir. Bu çalışmada insülinin hipokampal uzun dönemli baskılanma üzerine etkisi araştırılmıştır.
Metot: Bu çalışmada ağırlıkları 200-300 gr arasında değişen 24 adet Wistar erkek sıçan kullanılmıştır. Sıçanlar; Serum fizyolojik infüze edilen grup (SF, n=6), insülin infüze edilen grup (İnsülin, n=6), NT157 infüze edilen grup (NT157, n=6) ve insülin ile birlikte NT157 infüze edilen grup (İnsülin+NT157, n=6) olmak üzere dört gruba ayrılmıştır. Uzun dönemli baskılanma perforant yola uygulanan 1 Hz 900 adet düşük frekanslı uyarı (DFU) ile indüklenmiştir. Dentat girus granül hücrelerinden elde edilen alan potansiyellerinden eksitatör postsinaptik potansiyel (EPSP) eğimi ve populasyon spike (PS) genlikleri kaydedilmiştir. Deney bitiminde çıkarılan uyarılmış hipokampüslerde PI3K, AKT, GSK3-b, IRS ve MAPT gen ekspresyonu düzeyleri PCR yöntemi ile ölçülmüştür.
Bulgular: Perforan yolun 1 Hz ile uyarımı sonrası PS değerleri insülin infüze edilen grupta SF infüze edilen gruba karşı istatistiksel olarak anlamlı düşüş göstermiştir (p<0,05). NT157 infüze edilen grupta bu baskılanma ortadan kalkmıştır. İnsülin+NT157 verilen grupta AKT mRNA seviyeleri azalma göstermiş, NT157 infüze edilen grupta IRS mRNA seviyeleri artmıştır (p<0,001). Yalnızca insülin infüze edilen grupta GSK3-b mRNA seviyeleri artmış bulunmuştur.
Sonuç: Hipokampal granül hücrelerinden kaydedilen alan potansiyelleri değerleri, insülinin hipokampüste UDB’ yi kolaylaştırdığını göstermiştir. İnsülinin hipokampüs üzerine etkisinin anlaşılması metabolik ve dejeneratif hastalıklar arasındaki ilişkinin ortaya konması için gereklidir.

Ethical Statement

Yapılan çalışmada, araştırma ve yayın etiğine uyulmuştur.

Supporting Institution

Bu çalışma Erciyes Üniversitesi Bilimsel Araştırma Projeleri Birimi tarafından TDK-2021-11215 kodlu proje ile desteklenmiştir.

Project Number

TDK-2021-11215

Thanks

Bu çalışma Erciyes Üniversitesi Bilimsel Araştırma Projeleri Birimi tarafından TDK-2021-11215 kodlu proje ile desteklenmiştir.

References

  • 1. Banting, F.G., et al., Pancreatic extracts in the treatment of diabetes mellitus. Canadian Medical Association Journal, 1922. 12(3): p. 141.
  • 2. Havrankova, J., J. Roth, and M. BROWNSTEIN, Insulin receptors are widely distributed in the central nervous system of the rat. Nature, 1978. 272(5656): p. 827-829.
  • 3. Porte Jr, D., D.G. Baskin, and M.W. Schwartz, Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes, 2005. 54(5): p. 1264-1276.
  • 4. Lin, X., et al., Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes. The Journal of clinical investigation, 2004. 114(7): p. 908-916.
  • 5. Marks, J.L., M.G. King, and D.G. Baskin, Localization of insulin and type 1 IGF receptors in rat brain by in vitro autoradiography and in situ hybridization. Molecular biology and physiology of insulin and insulin-like growth factors, 1991: p. 459-470.
  • 6. Abbott, M.-A., D.G. Wells, and J.R. Fallon, The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. Journal of Neuroscience, 1999. 19(17): p. 7300-7308.
  • 7. Zhao, W., et al., Brain insulin receptors and spatial memory: correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. Journal of Biological Chemistry, 1999. 274(49): p. 34893-34902.
  • 8. Moosavi, M., et al., The effect of intrahippocampal insulin microinjection on spatial learning and memory. Hormones and behavior, 2006. 50(5): p. 748-752.
  • 9. Brands, A.M., et al., The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes care, 2005. 28(3): p. 726-735.
  • 10. 1Hishikawa, N., et al., Cognitive and affective functions in Alzheimer's disease patients with metabolic syndrome. European journal of neurology, 2016. 23(2): p. 339-345.
  • 11. 1Malenka, R.C. and M.F. Bear, LTP and LTD: an embarrassment of riches. Neuron, 2004. 44(1): p. 5-21.
  • 12. 1Bastrikova, N., et al., Synapse elimination accompanies functional plasticity in hippocampal neurons. Proceedings of the National Academy of Sciences, 2008. 105(8): p. 3123-3127.
  • 13. 1Labouèbe, G., et al., Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nature neuroscience, 2013. 16(3): p. 300-308.
  • 14. Lissin, D.V., et al., Rapid, activation-induced redistribution of ionotropic glutamate receptors in cultured hippocampal neurons. Journal of Neuroscience, 1999. 19(4): p. 1263-1272.
  • 15. Man, H.-Y., et al., Regulation of AMPA receptor–mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron, 2000. 25(3): p. 649-662.
  • 16. Beattie, E.C., et al., Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nature neuroscience, 2000. 3(12): p. 1291-1300.
  • 17. Wang, Y.T. and D.J. Linden, Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron, 2000. 25(3): p. 635-647.
  • 18. Holgado-Madruga, M., et al., A Grb2-associated docking protein in EGF-and insulin-receptor signalling. Nature, 1996. 379(6565): p. 560-564.
  • 19. Copps, K. and M. White, Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia, 2012. 55: p. 2565-2582.
  • 20. Li, C.X., et al., Repressing IRS1/2 by NT157 inhibits the malignant behaviors of ovarian cancer through inactivating PI3K/AKT/mTOR pathway and inducing autophagy. The Kaohsiung Journal of Medical Sciences, 2023. 39(4): p. 377-389.
  • 21. Bradley, C.A., et al., A pivotal role of GSK-3 in synaptic plasticity. Frontiers in molecular neuroscience, 2012. 5: p. 13.

Role of Insulin in Synaptic Plasticity; Long Term Depression

Year 2024, Volume: 46 Issue: 3, 455 - 462, 27.05.2024
https://doi.org/10.20515/otd.1400449

Abstract

Introduction: Insulin is a hormone secreted by pancreatic beta cells that is essential for maintaining glucose homeostasis. Although its peripheral effects have been elucidated in detail, its effect on cognitive function is unclear. The effect of insulin on long-term depression (LTD) of the hippocampus was examined in this study.
Method: In this study, 24 male Wistar rats weighing between 200-300 g were used. Rats were divided into four groups as saline-infused group (SF, n=6), insulin infused group (Insulin, n=6), the NT157-infused group (NT157, n=6), and insulin+NT157-infused group (Insulin+NT157, n=6). Long-term depression (LTD) was induced by 900 low-frequency stimuli (LFS) at 1 Hz applied to the perforant pathway. Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitudes were recorded from field potentials obtained from dentate gyrus granule cells. At the end of the experiment, PI3K, AKT, GSK3-b, IRS, and MAPT gene expression levels were measured by PCR in the stimulated hippocampi.
Results: After stimulation of the perforant path with 1 Hz, PS values showed a statistically significant decrease in the insulin-infused group compared to the SF-infused group (p<0.05). This depression was abolished in the NT157-infused group. AKT mRNA levels decreased in the insulin+NT157 group, whereas IRS mRNA levels increased in the NT157-infused group (p<0.001). GSK3-b mRNA levels were found to be increased in the insulin-infused group.
Conclusion: Field potentials recorded from hippocampal granule cells indicated that insulin facilitates LTD in the hippocampus. Understanding the effect of insulin on the hippocampus is necessary to elucidate the relationship between metabolic and degenerative diseases.

Project Number

TDK-2021-11215

References

  • 1. Banting, F.G., et al., Pancreatic extracts in the treatment of diabetes mellitus. Canadian Medical Association Journal, 1922. 12(3): p. 141.
  • 2. Havrankova, J., J. Roth, and M. BROWNSTEIN, Insulin receptors are widely distributed in the central nervous system of the rat. Nature, 1978. 272(5656): p. 827-829.
  • 3. Porte Jr, D., D.G. Baskin, and M.W. Schwartz, Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes, 2005. 54(5): p. 1264-1276.
  • 4. Lin, X., et al., Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes. The Journal of clinical investigation, 2004. 114(7): p. 908-916.
  • 5. Marks, J.L., M.G. King, and D.G. Baskin, Localization of insulin and type 1 IGF receptors in rat brain by in vitro autoradiography and in situ hybridization. Molecular biology and physiology of insulin and insulin-like growth factors, 1991: p. 459-470.
  • 6. Abbott, M.-A., D.G. Wells, and J.R. Fallon, The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. Journal of Neuroscience, 1999. 19(17): p. 7300-7308.
  • 7. Zhao, W., et al., Brain insulin receptors and spatial memory: correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. Journal of Biological Chemistry, 1999. 274(49): p. 34893-34902.
  • 8. Moosavi, M., et al., The effect of intrahippocampal insulin microinjection on spatial learning and memory. Hormones and behavior, 2006. 50(5): p. 748-752.
  • 9. Brands, A.M., et al., The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes care, 2005. 28(3): p. 726-735.
  • 10. 1Hishikawa, N., et al., Cognitive and affective functions in Alzheimer's disease patients with metabolic syndrome. European journal of neurology, 2016. 23(2): p. 339-345.
  • 11. 1Malenka, R.C. and M.F. Bear, LTP and LTD: an embarrassment of riches. Neuron, 2004. 44(1): p. 5-21.
  • 12. 1Bastrikova, N., et al., Synapse elimination accompanies functional plasticity in hippocampal neurons. Proceedings of the National Academy of Sciences, 2008. 105(8): p. 3123-3127.
  • 13. 1Labouèbe, G., et al., Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nature neuroscience, 2013. 16(3): p. 300-308.
  • 14. Lissin, D.V., et al., Rapid, activation-induced redistribution of ionotropic glutamate receptors in cultured hippocampal neurons. Journal of Neuroscience, 1999. 19(4): p. 1263-1272.
  • 15. Man, H.-Y., et al., Regulation of AMPA receptor–mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron, 2000. 25(3): p. 649-662.
  • 16. Beattie, E.C., et al., Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nature neuroscience, 2000. 3(12): p. 1291-1300.
  • 17. Wang, Y.T. and D.J. Linden, Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron, 2000. 25(3): p. 635-647.
  • 18. Holgado-Madruga, M., et al., A Grb2-associated docking protein in EGF-and insulin-receptor signalling. Nature, 1996. 379(6565): p. 560-564.
  • 19. Copps, K. and M. White, Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia, 2012. 55: p. 2565-2582.
  • 20. Li, C.X., et al., Repressing IRS1/2 by NT157 inhibits the malignant behaviors of ovarian cancer through inactivating PI3K/AKT/mTOR pathway and inducing autophagy. The Kaohsiung Journal of Medical Sciences, 2023. 39(4): p. 377-389.
  • 21. Bradley, C.A., et al., A pivotal role of GSK-3 in synaptic plasticity. Frontiers in molecular neuroscience, 2012. 5: p. 13.
There are 21 citations in total.

Details

Primary Language Turkish
Subjects Medical Pharmacology, Endocrinology
Journal Section ORİJİNAL MAKALE
Authors

Ercan Babur 0000-0003-1445-6423

Özlem Barutçu 0000-0002-6107-2599

Esra Tufan 0000-0003-3782-9085

Hatice Saray 0000-0002-8361-0618

Cem Süer 0000-0002-6455-6644

Project Number TDK-2021-11215
Publication Date May 27, 2024
Submission Date December 5, 2023
Acceptance Date May 14, 2024
Published in Issue Year 2024 Volume: 46 Issue: 3

Cite

Vancouver Babur E, Barutçu Ö, Tufan E, Saray H, Süer C. İnsülinin Sinaptik Plastisitedeki Rolü: Uzun Dönemli Baskılanma. Osmangazi Tıp Dergisi. 2024;46(3):455-62.


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