Possible Role of Akt in Mossy Fiber Sprouting: Akt Activity and CA3 Mossy Fiber Sprouting in a Kainate Model of Epilepsy
Akt Activity and CA3 Mossy Fiber Sprouting in Epilepsy
DOI:
https://doi.org/10.11594/jtls.14.03.09Keywords:
Akt, CA mossy fiber sprouting, Kainic acid, Organotypic hippocampal slice cultureAbstract
The most prevalent pathological phenomenon observed in patients with epilepsy is hippocampal mossy fiber sprouting (MFS), which is thought to be associated with epileptic progression, such as worsening seizure control, cognitive function, and behavior. MFS is discovered in the dentate gyrus and the hippocampal Cornu Ammon 3 (CA3) area. The CA3 area is involved in memory, so disturbances in that area can affect memory impairment in patients with epilepsy. The mammalian target of rapamycin complex-1 (mTORC1) is also associated with MFS. Akt is an upstream activator of mTORC1 and a downstream target of mammalian target of rapamycin complex-2 (mTORC2) and plays a role in cytoskeleton organization. We analyzed Akt activity and MFS in the CA3 zone in an in vitro model of kainate-induced epilepsy. We divided organotypic hippocampal slice cultures (OHSCs) into a kainate (epilepsy) group and a control (untreated) group. On the 10th day in vitro (DIV), the kainate group was exposed to 8 µM kainic acid for 48 h, diluted in the medium. At 32 DIV, we measured Akt activity through western blotting and CA3 MFS through synaptoporin fluorescence intensity observed using confocal laser scanning microscopy. We found that Akt activity increased significantly (p = 0.000) in the kainate group, and the synaptoporin fluorescence intensity also increased in the stratum oriens of the CA3 area (p = 0.049) in the kainate group. Our findings implied that Akt may play a role in MFS development. Because Akt is a main downstream target of mTORC2, mTORC2 may also be involved in MFS development. Further research is required to clarify these findings.
References
Buckmaster PS (2012) Mossy Fiber Sprouting in the Dentate Gyrus. In: Noebels JL, Avoli M, Rogawski MA , et al. ed Jasper’s Basic Mech. Epilepsies, 4th ed. Bethesda (MD), National Center for Biotechnology Information (US). 1–22.
Koyama R, Ikegaya Y (2004) Mossy Fiber Sprouting as a Potential Therapeutic Target for Epilepsy. Current Neurovascular Research 1 (1): 3–10. doi: 10.2174/1567202043480242.
Koyama R (2016) Dentate circuitry as a model to study epileptogenesis. Biological and Pharmaceutical Bulletin 39 (6): 891–896. doi: 10.1248/bpb.b16-00125.
Ostendorf AP, Wong M (2015) mTOR Inhibition in Epilepsy: Rationale and Clinical Perspectives. CNS Drugs 29 (2): 91–99. doi: 10.1007/s40263-014-0223-x.mTOR.
Coan AC, Cendes F (2013) Epilepsy as progressive disorders: What is the evidence that can guide our clinical decisions and how can neuroimaging help? Epilepsy and Behavior 26 (3): 313–321.doi: 10.1016/j.yebeh.2012.09.027.
Godale CM, Danzer SC (2018) Signaling Pathways and Cellular Mechanisms Regulating Mossy Fiber Sprouting in the Development of Epilepsy. Front Neurol. doi: 10.3389/fneur.2018.00298
Rami A, Niquet J, Konoplew A (2019) Early Aberrant Growth of Mossy Fibers after Status Epilepticus in the Immature Rat Brain. Molecular Neurobiology 56 (7): 5025–5031. doi: 10.1007/s12035-018-1432-y.
Koyama R, Ikegaya Y (2018) The molecular and cellular mechanisms of axon guidance in mossy fiber sprouting. Frontiers in Neurology 9 (MAY): 1–8. doi: 10.3389/fneur.2018.00382.
Pérez-Gómez A, Tasker RA (2014) Enhanced mossy fiber sprouting and synapse formation in organotypic hippocampal cultures following transient domoic acid excitotoxicity. Neurotoxicity Research 25 (4): 402–410. doi: 10.1007/s12640-013-9450-z.
Siddiqui AH, Joseph SA (2005) CA3 axonal sprouting in kainate-induced chronic epilepsy. Brain Research 1066 (1–2): 129–146. doi: 10.1016/j.brainres.2005.10.066.
Cherubini E, Miles R (2015) The CA3 region of the hippocampus: How is it? What is it for? How does it do it? Frontiers in Cellular Neuroscience 9 (FEB): 9–11. doi: 10.3389/fncel.2015.00019.
Thom M (2014) Review: Hippocampal sclerosis in epilepsy: A neuropathology review. Neuropathology and Applied Neurobiology 40 (5): 520–543. doi: 10.1111/nan.12150.
Barallobre MJ, Pascual M, Rio JoA Del, Soriano E (2005) The Netrin family of guidance factors : Emphasis on Netrin-1 signalling The Netrin family of guidance factors : emphasis on Netrin-1 signalling. Brain Research Review 49 22–47.doi: 10.1016/j.brainresrev.2004.11.003.
Hester MS, Danzer SC (2013) Accumulation of Abnormal Adult-Generated Hippocampal Granule Cells Predicts Seizure Frequency and Severity. Journal of Neuroscience 33 (21): 8926–8936. doi: 10.1523/JNEUROSCI.5161-12.2013.
Muramatsu R, Nakahara S, Ichikawa J, et al. (2010) The ratio of “deleted in colorectal cancer” to “uncoordinated-5A” netrin-1 receptors on the growth cone regulates mossy fibre directionality. Brain 133 (1): 60–75. doi: 10.1093/brain/awp266.
Song MY, Tian FF, Wang YZ, et al. (2015) Potential roles of the RGMa-FAK-Ras pathway in hippocampal mossy fiber sprouting in the pentylenetetrazole kindling model. Molecular Medicine Reports 11 (3): 1738–1744.doi: 10.3892/mmr.2014.2993.
Bracho-valdes I, Moreno-alvarez P, Valencia-martı I, et al. (2011) mTORC1- and mTORC2-interacting Proteins Keep Their Multifunctional Partners Focused. IUBMB Life 63 (October): 896–914. doi: 10.1002/iub.558.
Ihwah A, Deoranto P, Wijana S, Dewi IA (2018) Comparative study between Federer and Gomez method for number of replication in complete randomized design using simulation: Study of Areca Palm (Areca catechu) as organic waste for producing handicraft paper. IOP Conf Ser Earth Environ Sci. doi: 10.1088/1755-1315/131/1/012049
De Simoni A, Yu LMY (2006) Preparation of organotypic hippocampal slice cultures: Interface method. Nature Protocols 1 (3): 1439–1445. doi: 10.1038/nprot.2006.228.
Opitz-Araya X, Barria A (2011) Organotypic hippocampal Slice Cultures. Journal of Visualized Experiments (48): 35–37. doi: 10.3791/2462.
Velisek L (2006) Models of Chemically-Induced Acute Seizures. In: Pitkanen A, Schwartzkroin PA, Moshe SL eds Model. Seizures Epilepsy. San Diego, Elsevier Inc. 127–152.
Routbort MJ, Bausch SB, McNamara JO (1999) Seizures, cell death, and mossy fiber sprouting in kainic acid-treated organotypic hippocampal cultures. Neuroscience 94 (3): 755–765. doi: 10.1016/S0306-4522(99)00358-9.
Zhu J, Zheng XY, Zhang HL, Luo Q (2011) Kainic acid-induced neurodegenerative model: Potentials and limitations. J Biomed Biotechnol. doi: 10.1155/2011/457079
Bernard C (2006) Hippocampal Slices : Designing and Interpreting Studies in Epilepsy Research. In: Pitkanen A, Schwartzkroin PA, Moshe SL eds Model. Seizures Epilepsy. San Diego, Elsevier Inc. pp 59–72.
Bausch SB, McNamara JO (2004) Contributions of mossy fiber and CA1 pyramidal cell sprouting to dentate granule cell hyperexcitability in kainic acid-treated hippocampal slice cultures. Journal of Neurophysiology 92 (6): 3582–3595.doi: 10.1152/jn.01028.2003.
Dudek FE, Clark S, Williams PA, Grabenstatter HL (2006) Kainate-Induced Status Epilepticus: A Chronic Model of Acquired Epilepsy. In: Pitkanen A, Schwartzkroin PA, Moshe SL eds Model. Seizures Epilepsy. San Diego. pp 415–431.
Brandalise F, Gerber U (2014) Mossy fiber-evoked subthreshold responses induce timing-dependent plasticity at hippocampal CA3 recurrent synapses. Proceedings of the National Academy of Sciences of the United States of America 111 (11): 4303–4308. doi: 10.1073/pnas.1317667111.
Belvindrah R, Nosten-Bertrand M, Francis F (2014) Neuronal migration and its disorders affecting the CA3 region. Frontiers in Cellular Neuroscience 8 (MAR): 1–16. doi: 10.3389/fncel.2014.00063.
Chung J, Franklin JF, Lee HJ (2019) Central expression of synaptophysin and synaptoporin in nociceptive afferent subtypes in the dorsal horn. Scientific Reports 9 (1): 1–11. doi: 10.1038/s41598-019-40967-y.
Singec I, Knoth R, Ditter M, et al. (2002) Synaptic vesicle protein synaptoporin is differently expressed by subpopulations of mouse hippocampal neurons. Journal of Comparative Neurology 452 (2): 139–153. doi: 10.1002/cne.10371.
Song H, Mylvaganam SM, Wang J, et al. (2018) Contributions of the hippocampal CA3 circuitry to acute seizures and hyperexcitability responses in mouse models of brain ischemia. Frontiers in Cellular Neuroscience 12 (August): 1–21. doi: 10.3389/fncel.2018.00278.
Ikegaya Y (1999) Abnormal targeting of developing hippocampal mossy fibers after epileptiform activities via L-type Ca2+ channel activation in vitro. Journal of Neuroscience 19 (2): 802–812. doi: 10.1523/jneurosci.19-02-00802.1999.
Chong ZZ, Shang YC, Wang S, Maiese K (2012) A Critical Kinase Cascade in Neurological Disorders: PI 3-K, Akt, and mTOR. Future neurology 7 (6): 733–748. doi: 10.2217/fnl.12.72.
Zhu F, Kai J, Chen L, et al. (2018) Akt Inhibitor Perifosine Prevents Epileptogenesis in a Rat Model of Temporal Lobe Epilepsy. Neuroscience Bulletin 34 (2): 283–290. doi: 10.1007/s12264-017-0165-7.
Sen B, Xie Z, Case N, et al. (2014) mTORC2 regulates mechanically induced cytoskeletal reorganization and lineage selection in marrow-derived mesenchymal stem cells. J Bone Miner Res 29 (1): 1–20. doi: 10.1016/j.immuni.2010.12.017.Two-stage.
Driscoll DR, Karim SA, Sano M, et al. (2016) mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer. Cancer Res 76 (23): 6911–6924. doi: 10.1158/0008-5472.CAN-16-0810.
Lisi L, Aceto P, Navarra P, Russo C Dello (2015) mTOR Kinase : A Possible Pharmacological Target in the Management of Chronic Pain. BioMed Research International 2015 1–13.
Switon K, Kotulska K, Janusz-kaminska A, et al. (2017) MOLECULAR NEUROBIOLOGY OF mTOR. Neuroscience 341: 112–153. doi: 10.1016/j.neuroscience.2016.11.017.
Byrne KM, Monsefi N, Dawson JC, et al. (2016) Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches. Cell Systems 2 (1): 38–48. doi: 10.1016/j.cels.2016.01.003.
Henle SJ, Wang G, Liang E, et al. (2011) Asymmetric PI(3,4,5)P3 and Akt Signaling Mediates Chemotaxis of Axonal Growth Cones. The Journal of Neuroscience 31 (19): 7016 – 7027. doi: 10.1523/JNEUROSCI.0216-11.2011.
Levenga J, Wong H, Milstead RA, et al. (2017) AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity. eLife 6 1–24. doi: 10.7554/eLife.30640.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Journal of Tropical Life Science
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The work has not been published before (except in the form of an abstract or part of a published lecture or thesis) and it is not under consideration for publication elsewhere. When the manuscript is accepted for publication in this journal, the authors agree to automatic transfer of the copyright to the publisher.
Journal of Tropical Life Science is licensed under Creative Commons Attribution-NonCommercial 4.0 International License
