The Cellular and Synaptic Location of Activated TrkB in Mouse Hippocampus During Limbic Epileptogenesis

Overview

Journal J Comp Neurol

Specialty Neurology

Date 2012 Sep 19

PMID 22987780

Citations 10

Authors

Jeffrey Helgager

Gumei Liu

James O McNamara

Affiliations

Soon will be listed here.

Abstract

Understanding the mechanisms of limbic epileptogenesis in cellular and molecular terms may provide novel therapeutic targets for its prevention. The neurotrophin receptor tropomyosin-related kinase B (TrkB) is thought to be critical for limbic epileptogenesis. Enhanced activation of TrkB, revealed by immunodetection of enhanced phosphorylated TrkB (pTrkB), a surrogate measure of its activation, has been identified within the hippocampus in multiple animal models. Knowledge of the cellular locale of activated TrkB is necessary to elucidate its functional consequences. Using an antibody selective to pTrkB in conjunction with confocal microscopy and cellular markers, we determined the cellular and subcellular locale of enhanced pTrkB induced by status epilepticus (SE) evoked by infusion of kainic acid into the amygdala of adult mice. SE induced enhanced pTrkB immunoreactivity in two distinct populations of principal neurons within the hippocampus-the dentate granule cells and CA1 pyramidal cells. Enhanced immunoreactivity within granule cells was found within mossy fiber axons and giant synaptic boutons. By contrast, enhanced immunoreactivity was found within apical dendritic shafts and spines of CA1 pyramidal cells. A common feature of this enhanced pTrkB at these cellular locales is its localization to excitatory synapses between excitatory neurons, presynaptically in the granule cells and postsynaptically in CA1 pyramidal cells. Long-term potentiation (LTP) is one cellular consequence of TrkB activation at these excitatory synapses that may promote epileptogenesis.

Citing Articles

Progressive generalized tonic-clonic seizures in a transgenic mouse model of adult-onset epilepsy: Implications for morphological changes in cortico-limbic and brainstem structures.

Tyulmenkova A, Zwick A, Dillon T, Isgor C Epilepsy Res. 2023; 194:107178.

PMID: 37295319 PMC: 10527249. DOI: 10.1016/j.eplepsyres.2023.107178.

Long-Term Potentiation of Mossy Fiber Feedforward Inhibition of CA3 Pyramidal Cells Maintains E/I Balance in Epilepsy Model.

Pan E, Puranam R, McNamara J eNeuro. 2021; 9(1).

PMID: 34949685 PMC: 8805193. DOI: 10.1523/ENEURO.0375-21.2021.

Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure.

Krishnamurthy K, Huang Y, Harward S, Sharma K, Tamayo D, McNamara J Ann Neurol. 2019; 86(6):939-950.

PMID: 31525273 PMC: 7531259. DOI: 10.1002/ana.25602.

iPlasticity: Induced juvenile-like plasticity in the adult brain as a mechanism of antidepressants.

Umemori J, Winkel F, Didio G, Llach Pou M, Castren E Psychiatry Clin Neurosci. 2018; 72(9):633-653.

PMID: 29802758 PMC: 6174980. DOI: 10.1111/pcn.12683.

Hippocampal neuro-networks and dendritic spine perturbations in epileptogenesis are attenuated by neuroprotectin d1.

Musto A, Walker C, Petasis N, Bazan N PLoS One. 2015; 10(1):e0116543.

PMID: 25617763 PMC: 4305283. DOI: 10.1371/journal.pone.0116543.

References

Minichiello L . TrkB signalling pathways in LTP and learning. Nat Rev Neurosci. 2009; 10(12):850-60. DOI: 10.1038/nrn2738. View

Dunleavy M, Shinoda S, Schindler C, Ewart C, Dolan R, Gobbo O . Experimental neonatal status epilepticus and the development of temporal lobe epilepsy with unilateral hippocampal sclerosis. Am J Pathol. 2009; 176(1):330-42. PMC: 2797894. DOI: 10.2353/ajpath.2010.090119. View

Segal R, Bhattacharyya A, Rua L, Alberta J, Stephens R, Kaplan D . Differential utilization of Trk autophosphorylation sites. J Biol Chem. 1996; 271(33):20175-81. DOI: 10.1074/jbc.271.33.20175. View

Ishizuka N, Weber J, Amaral D . Organization of intrahippocampal projections originating from CA3 pyramidal cells in the rat. J Comp Neurol. 1990; 295(4):580-623. DOI: 10.1002/cne.902950407. View

Shimizu H, Fukaya M, Yamasaki M, Watanabe M, Manabe T, Kamiya H . Use-dependent amplification of presynaptic Ca2+ signaling by axonal ryanodine receptors at the hippocampal mossy fiber synapse. Proc Natl Acad Sci U S A. 2008; 105(33):11998-2003. PMC: 2575294. DOI: 10.1073/pnas.0802175105. View

Nicoll R, Schmitz D . Synaptic plasticity at hippocampal mossy fibre synapses. Nat Rev Neurosci. 2005; 6(11):863-76. DOI: 10.1038/nrn1786. View

Niewiadomska G, Mietelska-Porowska A, Mazurkiewicz M . The cholinergic system, nerve growth factor and the cytoskeleton. Behav Brain Res. 2010; 221(2):515-26. DOI: 10.1016/j.bbr.2010.02.024. View

Araki T, Simon R, Taki W, Lan J, Henshall D . Characterization of neuronal death induced by focally evoked limbic seizures in the C57BL/6 mouse. J Neurosci Res. 2002; 69(5):614-21. DOI: 10.1002/jnr.10356. View

Huang Y, Pan E, Xiong Z, McNamara J . Zinc-mediated transactivation of TrkB potentiates the hippocampal mossy fiber-CA3 pyramid synapse. Neuron. 2008; 57(4):546-58. DOI: 10.1016/j.neuron.2007.11.026. View

10.

He X, Kotloski R, Nef S, Luikart B, Parada L, McNamara J . Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron. 2004; 43(1):31-42. DOI: 10.1016/j.neuron.2004.06.019. View

11.

Walter C, Murphy B, Pun R, Spieles-Engemann A, Danzer S . Pilocarpine-induced seizures cause selective time-dependent changes to adult-generated hippocampal dentate granule cells. J Neurosci. 2007; 27(28):7541-52. PMC: 6672603. DOI: 10.1523/JNEUROSCI.0431-07.2007. View

12.

Minichiello L, Calella A, Medina D, Bonhoeffer T, Klein R, Korte M . Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron. 2002; 36(1):121-37. DOI: 10.1016/s0896-6273(02)00942-x. View

13.

Gruart A, Sciarretta C, Valenzuela-Harrington M, Delgado-Garcia J, Minichiello L . Mutation at the TrkB PLC{gamma}-docking site affects hippocampal LTP and associative learning in conscious mice. Learn Mem. 2007; 14(1):54-62. PMC: 1838546. DOI: 10.1101/lm.428307. View

14.

Schauwecker P, Steward O . Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci U S A. 1997; 94(8):4103-8. PMC: 20575. DOI: 10.1073/pnas.94.8.4103. View

15.

Kasugai M, Akaike K, Imamura S, Matsukubo H, Tojo H, Nakamura M . Differences in two mice strains on kainic acid-induced amygdalar seizures. Biochem Biophys Res Commun. 2007; 357(4):1078-83. DOI: 10.1016/j.bbrc.2007.04.067. View

16.

Arroyo S, Brodie M, Avanzini G, Baumgartner C, Chiron C, Dulac O . Is refractory epilepsy preventable?. Epilepsia. 2002; 43(4):437-44. DOI: 10.1046/j.1528-1157.2002.38501.x. View

17.

Binder D, Routbort M, Ryan T, Yancopoulos G, McNamara J . Selective inhibition of kindling development by intraventricular administration of TrkB receptor body. J Neurosci. 1999; 19(4):1424-36. PMC: 6786043. View

18.

Huber G, MATUS A . Differences in the cellular distributions of two microtubule-associated proteins, MAP1 and MAP2, in rat brain. J Neurosci. 1984; 4(1):151-60. PMC: 6564742. View

19.

Savage D, Rigsbee L, McNamara J . Knife cuts of entorhinal cortex: effects on development of amygdaloid kindling and seizure-induced decrease of muscarinic cholinergic receptors. J Neurosci. 1985; 5(2):408-13. PMC: 6565214. View

20.

Spencer-Segal J, Waters E, Bath K, Chao M, McEwen B, Milner T . Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage. J Neurosci. 2011; 31(18):6780-90. PMC: 3108038. DOI: 10.1523/JNEUROSCI.0910-11.2011. View