In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats

Çiğdem Özer; Burcu Sırmatel; Cemile Merve Seymen

doi:10.4274/atfm.galenos.2025.78608

Research Article

Eksojen BDNF Uygulamasının Dişi Sıçan Dentat Girus AMPA Reseptörüne In Vivo Etkisi

Year 2025, Volume: 79 Issue: 2, 93 - 105, 01.07.2025

Çiğdem Özer Burcu Sırmatel Cemile Merve Seymen

Abstract

Amaç: Önceki in vitro araştırmalar, beyin türevli nörotrofik faktörün (BDNF) α-amino-3-hidroksi-5-metil-4-izoksazol propiyonik asit (AMPA) ekspresyonunu ve sinaptik AMPA reseptörlerinin (AMPAR) trafiğini modüle ettiğini göstermiştir. Ancak, eksojen BDNF uygulamasının in vivo ortamda AMPAR trafiğini benzer şekilde düzenleyip düzenlemediği bilinmemektedir. Bu çalışma, bu bilinmeyeni aydınlatmayı amaçlamaktadır. Ayrıca BDNF ve östrojenin beyinde benzer etkilere sebep olması ve hücresel mekanizmalarının birbirini etkilemesi nedeniyle dişilere BDNF uygulamanın sonuçlarını gözlemlemek de hedeflenmiştir.

Gereç ve Yöntem: Aynı estrus evresindeki dişi Long-Evans sıçanları, deney grubu (DG, n=5) kontrol grubu (KG, n=5) olarak ayrılmıştır. DG sağ hipokampüslerine BDNF proteini (4 μg/gün), KG grubu sıçanlarınkine ise PBS (4 μg/gün), ozmotik minipompalar vasıtasıyla intrahipokampal olarak

Bulgular: Genel olarak davranış deneyi açısından gruplar arasında anlamlı farklılık gözlenmemesine rağmen H-skor sonuçlarına göre BDNF uygulaması DG’nin sağ (p≤0,001) hipokampusunda KG’ye kıyasla AMPAR alt birimi GluR1’in immünoreaktivitesini önemli ölçüde artırmıştır. Hatta GluR1 H-skor seviyeleri infüzyon alanı olmayan sol hemisferde de anlamlı olarak yükselmiştir (p≤0,001).

Sonuç: Bu çalışma, uzun süreli BDNF uygulamasının hipokampusta AMPAR seviyelerini artırdığını in vivo olarak göstermektedir. Bu artışın dişi sıçanlardaki mekansal öğrenme ve bellek sürecine davranışsal yansımaları olmakla birlikte anlamlı etkileri için ileri araştırmalara ihtiyaç duyulmaktadır.

Keywords

AMPA reseptörü, uzun-dönem potansiyasyon, beyin türevli nörotrofik faktör, öğrenme ve bellek, sinaptik plastisite

Ethical Statement

Ethics Committee Approval: This study was approved by the Gazi University Local Ethics Committee for Animal Experiments (decision no: E.28661, date: 16.08.2017). Informed Consent: In this study, we utilized adult female Long-Evans rats (n=10), each weighing between 200-250 g. The animals were obtained from the Gazi University Laboratory Animals Breeding and Experimental Research Center (GUDAM). All procedures involving the rats were conducted in the designated laboratory settings of GUDAM. Acknowledgments We would like to thank the expert and staff members at the Gazi University Laboratory Animal Breeding and Experimental Research Center. We also extend our gratitude to young researcher Batuhan Sözer for his contributions in preparing Python code for data analysis from the video recordings of the MWM task, which facilitated a detailed examination of this aspect of the study. Footnotes Authorship Contributions Surgical and Medical Practices: B.S.B., Concept: B.S.B., Ç.Ö., Design: B.S.B., Ç.Ö., Data Collection and/or Processing: B.S.B., C.M.S., Analysis and/or Interpretation: B.S.B., Ç.Ö., C.M.S., Literature Search: B.S.B., Ç.Ö., Writing: B.S.B., C.M.S. Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: This study is supported by the Gazi University Scientific Research Projects Coordination Unit with the decision number 01/2017-26.

Supporting Institution

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In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats

Year 2025, Volume: 79 Issue: 2, 93 - 105, 01.07.2025

Çiğdem Özer Burcu Sırmatel Cemile Merve Seymen

Abstract

Objectives: Previous in vitro studies have demonstrated that brain-derived neurotrophic factor (BDNF) modulates α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) expression and the trafficking of synaptic AMPA receptors (AMPARs). However, it is not known whether exogenous BDNF administration similarly regulates AMPAR trafficking in vivo. This study aims to elucidate this unknown aspect. Additionally, considering that BDNF and estrogen have similar effects in the brain and may interact through their cellular mechanisms, the study also aims to explore the outcomes of BDNF administration in female rats.

Material and Methods: For this purpose, female Long-Evans rats in the same estrus phase were divided into the experimental group (EG, n=5) and the control group (CG, n=5). In the EG, recombinant BDNF protein (4 μg/day) was administered to the right hippocampus via osmotic minipumps for 7 days, while the CG received phosphate-buffered saline (PBS) (4 μg/day) under the same conditions. The Morris Water Maze (MWM) test was employed for assessing learning and memory. AMPAR levels in the left and right hippocampi were examined using immunohistochemical methods, and the intensity patterns were evaluated using H-scoring.

Results: Although no significant behavioral differences were observed between the groups in the MWM task (p>0.05), H-scoring results revealed that BDNF treatment significantly increased GluR1 subunit immunoreactivity in the right hippocampus of the EG compared to the CG (p≤0.001). Notably, GluR1 H-score levels were also significantly increased in the left hemisphere, which was not directly infused with BDNF.

Conclusion: This study demonstrates that long-term BDNF administration increases AMPAR levels in the hippocampus in vivo. While this increase has behavioral implications for spatial learning and memory in female rats, further research is needed to explore the full extent of these effects.

Keywords

AMPA receptor, long-term potentiation, brain-derived neurotrophic factor, learning and memory, synaptic plasticity

References

1. Kandel ER, Schwards JH, Jessel TM, et al. Principles of neural science. 5th ed. New York, USA: McGrow Hill; 2013.
2. Lynch MA. Long-term potentiation and memory. Physiol Rev. 2004;84:87136.
3. Leal G, Afonso PM, Salazar IL, et al. Regulation of hippocampal synaptic plasticity by BDNF. Brain Res. 2015;1621:82-101.
4. Lu Y, Christian K, Lu B. BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem. 2008;89:312-323.
5. Anggono V, Huganir RL. Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol. 2012;22:461-469.
6. Bramham CR, Messaoudi E. BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol. 2005;76:99-125.
7. Jensen V, Kaiser KMM, Borchardt T, et al. A juvenile form of postsynaptic hippocampal long-term potentiation in mice deficienct for the AMPA receptor subunit GluR-A. J Physiol. 2003;553:843-856.
8. Lee HK, Takamiya K, He K, et al. Specific roles of AMPA receptor subunit GluR1 (GluA1) phosphorylation sites in regulating synaptic plasticity in the CA1 region of hippocampus. J Neurophysiol. 2010;103:479-489.
9. Lessmann V. Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol. 1998;31:667-674.
10. Lewin GR, Barde Y-A. Physiology of the neurotrophins. Annu Rev Neurosci. 1996;19:289-317.
11. Lewin GR, Carter BR. Neurotrophic factors. In: Lewin GR, Carter BR, authors. Handbook of experimental pharmacology. 49th vol. Berlin, Germany: Springer-Verlag; 2014. s.3-251.
12. Patterson SL, Pittenger C, Morozov A, et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron. 2001;32:123-140.
13. Minichiello L, Korte M, Wolfer D, et al. Essential role for TrkB receptors in hippocampus-mediated learning below a certain threshold before behavioral defects become apparent. neuron. 1999;24:401-414.
14. Korte M, Griesbeck O, Gravel C, et al. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc Natl Acad Sci U S A. 1996;93:1254712552.
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18. Xu B, Michalski B, Racine RJ, et al. The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes. Neuroscience. 2004;126:521-531.
19. Scharfman H, Goodman J, Macleod A, et al. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192:348-356.
20. Ye Y, Wang G, Wang H, et al. Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression. Neurosci Lett. 2011;503:15-19.
21. Narisawa-Saito M, Silva AJ, Yamaguchi T, et al. Growth factor-mediated Fyn signaling regulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression in rodent neocortical neurons. Proc Natl Acad Sci USA. 1999;96:2461-2466.
22. Itami C, Kimura F, Kohno T, et al. Brain-derived neurotrophic factordependent unmasking of “silent” synapses in the developing mouse barrel cortex. Proc Natl Acad Sci U S A. 2003;100:13069-13074.
23. Narisawa-Saito M, Iwakura Y, Kawamura M, et al. Brain-derived neurotrophic factor regulates surface expression of α-amino-3-hydroxy-5-methyl-4isoxazoleproprionic acid receptors by enhancing the N-ethylmaleimidesensitive factor/GLuR2 interaction in developing neocortical neurons. J Biol Chem. 2002;277:40910.
24. Jourdi H, Iwakura Y, Narisawa-Saito M, et al. Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptorassociated PDZ proteins in developing cortical neurons. Dev Biol. 2003;263:216-230.
25. Caldeira MV, Melo CV, Pereira DB, et al. Brain-derived neurotrophic factor regulates the expression and synaptic delivery of α-amino-3-hydroxy5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons. J Biol Chem. 2007;282:12619-12628. Erratum in: J Biol Chem. 2007;282:27556.
26. Li W, Keifer J. BDNF-induced synaptic delivery of AMPAR subunits is differentially dependent on NMDA receptors and requires ERK. Neurobiol Learn Mem. 2009;91:243-249.
27. Jourdi H, Kabbaj M. Acute BDNF treatment upregulates GluR1-SAP97 and GluR2-GRIP1 interactions: implications for sustained AMPA receptor expression. PLoS One. 2013;8:e57124.
28. Liu F, Day M, Muñiz LC, et al. Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci. 2008;11:334-343.
29. Woolley CS. Estrogen-mediated structural and functional synaptic plasticity in the female rat hippocampus. Horm Behav. 1998;34:140-8.
30. Levin ER. Cellular functions of plasma membrane estrogen receptors. Steroids. 2002;67:471-475.
31. Scharfman HE, Maclusky NJ. Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue? Trends Neurosci. 2005;28:79-85.
32. Zhou J, Zhang H, Cohen R, et al. Effects of estrogen treatment on expression of brain-derived neurotrophic factor and cAMP response element-binding protein expression and phosphorylation in rat amygdaloid and hippocampal structures. Neuroendocrinology. 2005;81:294-310.
33. Allen A, McCarson K. Estrogen increases nociception-evoked brain-derived neurotrophic factor gene expression in the female rat. Neuroendocrinology. 2005;81:193-199.
34. Sohrabji F, Lewis DK. Estrogen-BDNF interactions: implications for neurodegenerative diseases. Front Neuroendocrinol. 2006;27:404-14.
35. Bimonte-Nelson H, Nelson M, Granholm AG. Progesterone counteracts estrogen-induced increases in neurotrophins in the aged female rat brain. Neuroreport. 2004;15:2659-2663.
36. Gibbs R. Levels of trkA and BDNF mRNA, but not NGF mRNA, Fluctuate across the estrous cycle and increase in response to acute hormone replacement. Brain Res. 1998;787:259-268.
37. Cavus I, Duman R, Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats. Biol. Psychiatry. 2003;54:59-69.
38. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006;1:848858.
39. Lebron-Milad K, Milad MR. Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders. Biol Mood Anxiety Disord. 2012;7:2-3.
40. Mamounas LA, Altar CA, Blue ME, et al. BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci. 2000;20:771-782.
41. Paxinos, G, Watson C. The rat brain in stereotaxic coordinates. 4th ed. San Diego, CA, USA: Academic Press Inc; 1998.
42. D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Rev. 2001;36:60-90.
43. Ünal SG, Take G, Erdoğan D, et al. The effect of di-n-butyl phthalate on testis and the potential protective effects of resveratrol. Toxicol Ind Health. 2016;32:777-790.
44. Tomar, S. Converting video formats with FFmpeg. Linux Journal. 2006;146:10.
45. Wada, K. Image polygonal annotation with Python (polygon, rectangle, circle, line, point and image-level flag annotation). 2018. Available from: https://github.com/wkentaro/labelme
46. van Rossum, Guido. Python Reference Manual. Department of Computer Science [CS]. Centrum voor Wiskunde en Informatica (CWI). Amsterdam; 1995.
47. JASP Team, JASP [Computer software]. Version 0.18.3; 2024. Available from: https://jasp-stats.org/
48. Leal G, Comprido D, Duarte CB BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology. 2014;76:639-656.
49. Fortin DA, Srivastava T, Dwarakanath D, et al. Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation of GluA1-containing calcium-permeable AMPA receptors. J Neurosci. 2012;32:8127-8137.
50. Bi R, Broutman G, Foy MR, et al. The tyrosine kinase and mitogenactivated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci U S A. 2000;97:3602-3607.
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There are 73 citations in total.

Details

Primary Language	English
Subjects	Computational Neuroscience
Journal Section	Articles
Authors	Çiğdem Özer 0000-0002-2705-4522 Burcu Sırmatel 0000-0002-8061-2618 Cemile Merve Seymen 0000-0002-8945-3801
Publication Date	July 1, 2025
Submission Date	April 1, 2025
Acceptance Date	June 30, 2025
Published in Issue	Year 2025 Volume: 79 Issue: 2

Cite

APA	Özer, Ç., Sırmatel, B., & Seymen, C. M. (2025). In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats. Ankara Üniversitesi Tıp Fakültesi Mecmuası, 79(2), 93-105. https://doi.org/10.4274/atfm.galenos.2025.78608
AMA	Özer Ç, Sırmatel B, Seymen CM. In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats. Ankara Üniversitesi Tıp Fakültesi Mecmuası. July 2025;79(2):93-105. doi:10.4274/atfm.galenos.2025.78608
Chicago	Özer, Çiğdem, Burcu Sırmatel, and Cemile Merve Seymen. “In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats”. Ankara Üniversitesi Tıp Fakültesi Mecmuası 79, no. 2 (July 2025): 93-105. https://doi.org/10.4274/atfm.galenos.2025.78608.
EndNote	Özer Ç, Sırmatel B, Seymen CM (July 1, 2025) In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats. Ankara Üniversitesi Tıp Fakültesi Mecmuası 79 2 93–105.
IEEE	Ç. Özer, B. Sırmatel, and C. M. Seymen, “In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats”, Ankara Üniversitesi Tıp Fakültesi Mecmuası, vol. 79, no. 2, pp. 93–105, 2025, doi: 10.4274/atfm.galenos.2025.78608.
ISNAD	Özer, Çiğdem et al. “In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats”. Ankara Üniversitesi Tıp Fakültesi Mecmuası 79/2 (July 2025), 93-105. https://doi.org/10.4274/atfm.galenos.2025.78608.
JAMA	Özer Ç, Sırmatel B, Seymen CM. In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2025;79:93–105.
MLA	Özer, Çiğdem et al. “In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats”. Ankara Üniversitesi Tıp Fakültesi Mecmuası, vol. 79, no. 2, 2025, pp. 93-105, doi:10.4274/atfm.galenos.2025.78608.
Vancouver	Özer Ç, Sırmatel B, Seymen CM. In Vivo Effects of Exogenous BDNF Administration on AMPA Receptors in the Dentate Gyrus of Female Rats. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2025;79(2):93-105.

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