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JNK Isoforms Are Involved in the Control of Adult Hippocampal Neurogenesis in Mice, Both in Physiological Conditions and in an Experimental Model of Temporal Lobe Epilepsy

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Abstract

Neurogenesis in the adult dentate gyrus (DG) of the hippocampus allows the continuous generation of new neurons. This cellular process can be disturbed under specific environmental conditions, such as epileptic seizures; however, the underlying mechanisms responsible for their control remain largely unknown. Although different studies have linked the JNK (c-Jun-N-terminal-kinase) activity with the regulation of cell proliferation and differentiation, the specific function of JNK in controlling adult hippocampal neurogenesis is not well known. The purpose of this study was to analyze the role of JNK isoforms (JNK1/JNK2/JNK3) in adult-hippocampal neurogenesis. To achieve this goal, we used JNK-knockout mice (Jnk1−/−, Jnk2−/−, and Jnk3−/−), untreated and treated with intraperitoneal injections of kainic acid (KA), as an experimental model of epilepsy. In each condition, we identified cell subpopulations at different stages of neuronal maturation by immunohistochemical specific markers. In physiological conditions, we evidenced that JNK1 and JNK3 control the levels of one subtype of early progenitor cells (GFAP+/Sox2+) but not the GFAP+/Nestin+ cell subtype. Moreover, the absence of JNK1 induces an increase of immature neurons (Doublecortin+; PSA-NCAM+ cells) compared with wild-type (WT). On the other hand, Jnk1−/− and Jnk3−/− mice showed an increased capacity to maintain hippocampal homeostasis, since calbindin immunoreactivity is higher than in WT. An important fact is that, after KA injection, Jnk1−/− and Jnk3−/− mice show no increase in the different neurogenic cell subpopulation analyzed, in contrast to what occurs in WT and Jnk2−/− mice. All these data support that JNK isoforms are involved in the adult neurogenesis control.

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Abbreviations

ABC:

avidin-biotin-peroxidase complex

CB:

calbindin

CR:

calretinin

CT:

control

CBP:

Calcium-binding protein

DAB:

diaminobenzidine

DCX:

doublecortin

DG:

dentate gyrus

FBS:

fetal bovine serum

GCL:

granular cell layer

GC:

granule cells

GFAP:

glial fibrillary acidic protein

i.p:

intraperitoneal injection

IR:

immunoreactive

JNKs:

c-Jun N-terminal kinases

JNK1, JNK2, and JNK3:

JNK isoforms

jnk1 :

Knockout mice for JNK1

jnk2 −/− :

knockout mice for JNK2

jnk3 :

knockout mice for JNK3

KA:

kainic acid

KO:

knockout

NSC:

neural stem cells

O/N:

overnight

PB:

phosphate buffer

PBS:

phosphate-buffered saline

PSA-NCAM:

polysialic acid neural cell adhesion molecule

RT:

room temperature

SD:

standard deviation

SDA-PAGE:

sodium dodecyl sulfate polyacrylamide gel electrophoresis.

SDS:

sodium dodecyl sulfate

SEM:

standard error of mean

SGZ:

subgranular zone

TLE:

temporal lobe epilepsy

WT:

wild type

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Acknowledgements

This work was supported by Ministerio Español de Ciencia e Innovación, SAF2017-84283-R; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) CB06/05/0024; Consejo Nacional de Ciéncia y Tecnologia, CONACYT, 177594; Generalitat de Catalunya, 2014SGR-525; Generalitat de Catalunya, 2017 SGR 625; Postdoctoral Fellowship CONACYT-MEXICO, 298337; Doctoral Program in Sciences in Molecular Biology in Medicine LGAC; and Molecular Bases of Chronic-Degenerative Diseases and its Applications 000091, PNPC, CONACYT-MEXICO.

Thanks to Kyra -Mae Leighton for her technical support.

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Author notes

  1. Carme Auladell and Ester Verdaguer contributed equally to this work.

Authors and Affiliations

  1. Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

    Rubén D. Castro-Torres, Jon Landa, Marina Rabaza, Carme Auladell & Ester Verdaguer

  2. Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain

    Rubén D. Castro-Torres, Oriol Busquets, Miren Ettcheto & Antoni Camins

  3. Departamento de Biología Celular y Molecular, Laboratorio de Regeneración Neural, C.U.C.B.A, Universidad de Guadalajara, 44340, Jalisco, Mexico

    Rubén D. Castro-Torres & Carlos Beas-Zarate

  4. Departament de Bioquímica i Biotecnologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain

    Oriol Busquets, Miren Ettcheto & Jaume Folch

  5. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    Oriol Busquets, Miren Ettcheto, Jaume Folch, Antoni Camins, Carme Auladell & Ester Verdaguer

  6. Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Oriol Busquets, Miren Ettcheto, Antoni Camins, Carme Auladell & Ester Verdaguer

  7. Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, 5 Poniente No. 1670, 3460000, Talca, Chile

    Jordi Olloquequi

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  1. Rubén D. Castro-Torres
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Figure S1

Supplement Quantification of the number of DCX/CR positive cells and the representative histogram. *P < 0.05, ****P < 0.0001, vs WT CT and; &P < 0.05 vs genotype control. (PNG 40 kb)

High resolution image (TIF 54 kb)

Figure S2

Supplement A. Representative DG hippocampal images of double immune-label NeuN (Green) and PSA-NCAM cells (Red), from control mice (A, C, E, G) and 24 h KA treated mice (B, D, F, H) of WT, jnk1−/−, jnk2−/−−, jnk3−/−. Arrows show the double immuno-positive cells against NeuN and PSA-NCAM. B. Quantification of the number of double NeuN/PSA-NCAM positive cells and the representative histogram is displayed. In all conditions the levels of double labeled cells is low. Only an icrease is observed after KA in WT. **P < 0.01, vs WT CT. ZSG: stratum granular; h: hilus. A-H: Scale bar 50 μm. (PNG 5361 kb)

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Castro-Torres, R.D., Landa, J., Rabaza, M. et al. JNK Isoforms Are Involved in the Control of Adult Hippocampal Neurogenesis in Mice, Both in Physiological Conditions and in an Experimental Model of Temporal Lobe Epilepsy. Mol Neurobiol 56, 5856–5865 (2019). https://doi.org/10.1007/s12035-019-1476-7

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