Lrp4 in hippocampal astrocytes serves as a negative feedback factor in seizures

Springer Science and Business Media LLC - 2020
Zheng Yu1, Meiying Zhang2, Bin Luo3, Hongyang Jing3, Yue Yu4, Shunqi Wang3, Shunjing Luo5
1Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
2Nanchang University Hospital, Nanchang University, Nanchang, 330006, Jiangxi, China
3Institute of Life Science and School of Life Sciences, Nanchang University, Nanchang, 330006, Jiangxi, China
4Teensen Genesis School, Nanchang, 330006, Jiangxi, China
5Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, 17 Yongwai Street, Donghuo Distinct, Nanchang, 330006, Jiangxi, China

Tóm tắt

Abstract Background Epilepsy is characterized by the typical symptom of seizure, and anti-seizure medications are the main therapeutic method in clinical, but the effects of these therapy have not been satisfactory. To find a better treatment, it makes sense to further explore the regulatory mechanisms of seizures at genetic level. Lrp4 regionally expresses in mice hippocampus where is key to limbic epileptogenesis. It is well known that neurons release a high level of glutamate during seizures, and it has been reported that Lrp4 in astrocytes down-regulates glutamate released from neurons. However, it is still unclear whether there is a relationship between Lrp4 expression level and seizures, and whether Lrp4 plays a role in seizures. Results We found that seizures induced by pilocarpine decreased Lrp4 expression level and increased miR-351-5p expression level in mice hippocampus. Glutamate reduced Lrp4 expression and enhanced miR-351-5p expression in cultured hippocampal astrocytes, and these effects can be partially attenuated by AP5. Furthermore, miR-351-5p inhibitor lessened the reduction of Lrp4 expression in glutamate treated hippocampal astrocytes. Local reduction of Lrp4 in hippocampus by sh Lrp4 lentivirus injection in hippocampus increased the threshold of seizures in pilocarpine or pentylenetetrazol (PTZ) injected mice. Conclusions These results indicated that high released glutamate induced by seizures down-regulated astrocytic Lrp4 through increasing miR-351-5p in hippocampal astrocytes via activating astrocytic NMDA receptor, and locally reduction of Lrp4 in hippocampus increased the threshold of seizures. Lrp4 in hippocampal astrocytes appears to serve as a negative feedback factor in seizures. This provides a new potential therapeutic target for seizures regulation.

Từ khóa


Tài liệu tham khảo

Saxena S, Li S. Defeating epilepsy: a global public health commitment. Epilepsia Open. 2017;2:153–5.

Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55:475–82.

Devinsky O, Spruill T, Thurman D, Friedman D. Recognizing and preventing epilepsy-related mortality: a call for action. Neurology. 2016;86:779–86.

Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet. 2006;367:1087–100.

Tian N, Boring M, Kobau R, Zack MM, Croft JB. Active epilepsy and seizure control in adults—United States, 2013 and 2015. MMWR Morb Mortal Wkly Rep. 2018;67:437–42.

Zhang B, Luo SW, Wang Q, Suzuki T, Xiong WC, Mei L. LRP4 serves as a coreceptor of agrin. Neuron. 2008;60:285–97.

Pohlkamp T, Durakoglugil M, Lane-Donovan C, Xian X, Johnson EB, Hammer RE, et al. Lrp4 domains differentially regulate limb/brain development and synaptic plasticity. PLoS ONE. 2015;10:e0116701.

Sun XD, Li L, Liu F, Huang ZH, Bean JC, Jiao HF, et al. Lrp4 in astrocytes modulates glutamatergic transmission. Nat Neurosci. 2016;19:1010–8.

Choi HY, Dieckmann M, Herz J, Niemeier A. Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. PLoS ONE. 2009;4(11):e7930.

Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286:19489–500.

Xiong L, Jung JU, Wu HT, Xia WF, Pan JX, Shen CY, et al. Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption. Proc Natl Acad Sci USA. 2015;112:3487–92.

Ahn Y, Sims C, Logue JM, Weatherbee SD, Krumlauf R. Lrp4 and wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling. Development. 2013;140:583–93.

Tanahashi H, Tian QB, Hara Y, Sakagami H, Endo S, Suzuki T. Polyhydramnios in Lrp4 knockout mice with bilateral kidney agenesis: defects in the pathways of amniotic fluid clearance. Sci Rep. 2016;6:20241.

Li L, Xiong WC, Mei L. Neuromuscular junction formation, aging, and disorders. Annu Rev Physiol. 2018;80:159–88.

Eilam R, Pinkas-Kramarski R, Ratzkin BJ, Segal M, Yarden Y. Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain. Proc Natl Acad Sci USA. 1998;95:1888–93.

Liu X, Bates R, Yin DM, Shen C, Wang F, Su N, et al. Specific regulation of NRG1 isoform expression by neuronal activity. J Neurosci. 2011;31:8491–501.

Cavalheiro EA. The pilocarpine model of epilepsy. Ital J Neurol Sci. 1995;16:33–7.

Alachkar A, Azimullah S, Ojha SK, Beiram R, Lazewska D, Kiec-Kononowicz K, et al. The neuroprotective effects of histamine H3 receptor antagonist E177 on pilocarpine-induced status epilepticus in rats. Molecules. 2019;24:4106.

Curia G, Longo D, Biagini G, Jones RS, Avoli M. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods. 2008;172:143–57.

Biagini G, Avoli M, Marcinkiewicz J, Marcinkiewicz M. Brain-derived neurotrophic factor superinduction parallels anti-epileptic–neuroprotective treatment in the pilocarpine epilepsy model. J Neurochem. 2001;76:1814–22.

Baj G, Del Turco D, Schlaudraff J, Torelli L, Deller T, Tongiorgi E. Regulation of the spatial code for BDNF mRNA isoforms in the rat hippocampus following pilocarpine-treatment: a systematic analysis using laser microdissection and quantitative real-time PCR. Hippocampus. 2013;23:413–23.

Smolders I, Khan GM, Manil J, Ebinger G, Michotte Y. NMDA receptor-mediated pilocarpine-induced seizures: characterization in freely moving rats by microdialysis. Br J Pharmacol. 1997;121:1171–9.

Costa MS, Rocha JB, Perosa SR, Cavalheiro EA, Naffah-Mazzacoratti MG. Pilocarpine-induced status epilepticus increases glutamate release in rat hippocampal synaptosomes. Neurosci Lett. 2004;356:41–4.

Wu H, Friedman WJ, Dreyfus CF. Differential regulation of neurotrophin expression in basal forebrain astrocytes by neuronal signals. J Neurosci Res. 2004;76:76–85.

Lee RC, Feinbaum RL, Ambros V. The C-elegans heterochronic gene Lin-4 encodes small RNAs with antisense complementarity to Lin-14. Cell. 1993;75:843–54.

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

Gorter JA, Iyer A, White I, Colzi A, van Vliet EA, Sisodiya S, et al. Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. Neurobiol Dis. 2014;62:508–20.

Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012;69:445–51.

Shen C, Lu Y, Zhang B, Figueiredo D, Bean J, Jung J, et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest. 2013;123:5190–202.

Fisher RS, van Emde BW, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46:470–2.

Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun. 2015;6:6606.

Vezzani A, Baram TZ. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy Curr. 2007;7:45–50.

Heinemann U, Kaufer D, Friedman A. Blood-brain barrier dysfunction, TGFbeta signaling, and astrocyte dysfunction in epilepsy. Glia. 2012;60:1251–7.

Oyrer J, Maljevic S, Scheffer IE, Berkovic SF, Petrou S, Reid CA. Ion channels in genetic epilepsy: from genes and mechanisms to disease-targeted therapies. Pharmacol Rev. 2018;70:142–73.

Fukata Y, Fukata M. Epilepsy and synaptic proteins. Curr Opin Neurobiol. 2017;45:1–8.

Binder DK, Croll SD, Gall CM, Scharfman HE. BDNF and epilepsy: too much of a good thing? Trends Neurosci. 2001;24:47–53.

Liu G, Gu B, He XP, Joshi RB, Wackerle HD, Rodriguiz RM, et al. Transient inhibition of TrkB kinase after status epilepticus prevents development of temporal lobe epilepsy. Neuron. 2013;79:31–8.

Pun RYK, Rolle IJ, LaSarge CL, Hosford BE, Rosen JM, Uhl JD, et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron. 2012;75:1022–34.

Woo RS, Li XM, Tao Y, Carpenter-Hyland E, Huang YZ, Weber J, et al. Neuregulin-1 enhances depolarization-induced GABA release. Neuron. 2007;54:599–610.

Patel DC, Tewari BP, Chaunsali L, Sontheimer H. Neuron-glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci. 2019;20:282–97.

Boison D. The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol. 2008;84:249–62.

Ernfors P, Bengzon J, Kokaia Z, Persson H, Lindvall O. Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron. 1991;7:165–76.

Tan GH, Liu YY, Hu XL, Yin DM, Mei L, Xiong ZQ. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci. 2012;15:258–66.

Wu H, Xiong WC, Mei L. To build a synapse: signaling pathways in neuromuscular junction assembly. Development. 2010;137:1017–33.

Mohseni P, Sung HK, Murphy AJ, Laliberte CL, Pallari HM, Henkelman M, et al. Nestin is not essential for development of the CNS but required for dispersion of acetylcholine receptor clusters at the area of neuromuscular junctions. J Neurosci. 2011;31:11547–52.

Brenner HR, Akaaboune M. Recycling of acetylcholine receptors at ectopic postsynaptic clusters induced by exogenous agrin in living rats. Dev Biol. 2014;394:122–8.

Basu S, Sladecek S, Martinez de la Pena y Valenzuela I, Akaaboune M, Smal I, Martin K, et al. CLASP2-dependent microtubule capture at the neuromuscular junction membrane requires LL5beta and actin for focal delivery of acetylcholine receptor vesicles. Mol Biol Cell. 2015;26:938–51.

Zhang H, Sathyamurthy A, Liu F, Li L, Zhang L, Dong Z, et al. Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice. Elife. 2019;8:e45303.

Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Thông tin tác giả