Effects of BDNF deficiency and endoplasmic reticulum stress on the GABAergic system

Year 2021, Volume: 14 Issue: 4, 792 - 802, 01.10.2021

Gulay Hacıoğlu , Selma Cırrık , Hakan Yüzüak , Selcen Aydın İsmail Abidin

https://doi.org/10.31362/patd.834832

Abstract

Purpose: Protective pathways against endoplasmic reticulum stress in neurons are activated via brain-derived neurotrophic factor. However, it is not known how the inhibitory intermediate neuron types expressing the different Ca2+-binding proteins of GABAergic system will be affected with changes in Ca2+ homeostasis, in conditions of chronic reduction of brain-derived neurotrophic factor and endoplasmic reticulum stress. The study was planned to reveal the interaction of these factors.
Materials and methods: 6-8 months old (30-40 g), wild-type (WT) and brain-derived neurotrophic factor heterozygous (BDNF(+/-)) male mice were used and 4 groups were formed. Groups 3 and 4 were treated with a single dose of tunicamycin to induce endoplasmic reticulum stress. On the 3rd day of tunicamycin injection, animals were sacrificed and blood and brain tissues were taken. In serum samples BDNF, in tissue homogenates GRP78, CHOP, Caspase-12, parvalbumin, calretinin, calbindin, GAD65 and GAD67 levels were investigated by ELISA method. One-way ANOVA and Tukey post-hoc tests were used for statistical evaluation.
Results: Serum BDNF levels were significantly lower in BDNF(+/-) and tunicamycin-treated BDNF(+/-) groups. Caspase-12 and CHOP levels significantly increased with tunicamycin injection. Calbindin level decreased significantly with endoplasmic reticulum stress. GAD65 and GAD67 levels were similar in WT and BDNF(+/-) groups. However, GAD65 level was significantly decreased during endoplasmic reticulum stress in WT and BDNF(+/-) groups.
Conclusion: Endoplasmic reticulum stress caused a significant decrease in glutamic acid decarboxylase GAD65 isoform and caldindin levels. This result indicates that the sensitivity of varied intermediate neurons in GABAergic system to endoplasmic reticulum stress may be different.

Keywords

BDNF, Endoplasmic reticulum stress, Calcium homeostasis, GABA

Supporting Institution

Giresun Üniversitesi

Project Number

SAĞ-BAP-A-230218-85

BDNF eksikliği ve endoplazmik retikulum stresinin GABAerjik sistem üzerindeki etkileri

Abstract

Amaç: Nöronlarda endoplazmik retikulum stresine karşı koruyucu yollar, beyin kaynaklı nörotrofik faktör aracılığıyla etkinleştirilir. Bununla birlikte, GABAerjik sistemin farklı Ca2+-bağlayıcı proteinlerini eksprese eden inhibitör ara nöron tiplerinin, beyin kaynaklı nörotrofik faktörün kronik azalması ve endoplazmik retikulum stres koşullarında Ca2+ homeostazındaki değişikliklerden nasıl etkileneceği bilinmemektedir. Çalışma, bu faktörlerin etkileşimini ortaya çıkarmak için planlandı.
Gereç ve yöntem: 6-8 aylık (30-40 gr), yabanıl tip (WT) ve beyin kaynaklı nörotrofik faktör heterozigot (BDNF(+/-)) erkek fareler kullanılmış ve 4 grup oluşturulmuştur. Grup 3 ve 4, endoplazmik retikulum stresini indüklemek için tek doz tunikamisin ile muamele edildi. Tunikamisin enjeksiyonunun 3. gününde hayvanlar feda edilerek kan ve beyin dokuları alındı. Serum örneklerinde BDNF, doku homojenatlarında GRP78, CHOP, Kaspaz-12, parvalbumin, kalretinin, kalbindin, GAD65 ve GAD67 düzeyleri ELISA yöntemi ile analiz edildi. İstatistiksel değerlendirme için tek yönlü ANOVA ve Tukey post-hoc testleri kullanıldı.
Bulgular: Serum BDNF seviyeleri, BDNF(+/-) ve tunikamisin ile tedavi edilen BDNF(+/-) gruplarında anlamlı olarak daha düşüktü. Tunikamisin enjeksiyonu ile Kaspaz-12 ve CHOP seviyeleri önemli ölçüde artmıştır. Kalbindin düzeyi endoplazmik retikulum stresi ile önemli ölçüde azaldı. GAD65 ve GAD67 seviyeleri WT ve BDNF(+/-) gruplarında yakındı. Ancak WT ve BDNF(+/-) gruplarında endoplazmik retikulum stresi sırasında GAD65 düzeyi anlamlı olarak azaldı.
Sonuç: Endoplazmik retikulum stresi glutamik asit dekarboksilazın GAD65 izoformunda ve kalbindin düzeylerinde anlamlı bir düşüşe sebep olmuştur. Bu sonuç, GABAerjik sistemdeki çeşitli ara nöronların endoplazmik retikulum stresine duyarlılıklarının farklı olabileceğini göstermektedir.

Keywords

BDNF, Endoplazmik retikulum stresi, Kalsiyum homeostazı, GABA

Project Number

SAĞ-BAP-A-230218-85

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