Neuritin Mediates Activity-Dependent Axonal Branch Formation in Part via FGF Signaling.
Aberrant branch formation of granule cell axons (mossy fiber sprouting) is observed in the dentate gyrus of many patients with temporal lobe epilepsy and in animal models of epilepsy. However, the mechanisms underlying mossy fiber sprouting remain elusive. Based on the hypothesis that seizure-mediated gene expression induces abnormal mossy fiber growth, we screened activity-regulated genes in the hippocampus and found that neuritin, an extracellular protein anchored to the cell surface, was rapidly upregulated after electroconvulsive seizures. Overexpression of neuritin in the cultured rat granule cells promoted their axonal branching. Also, kainic acid-dependent axonal branching was abolished in the cultured granule cells fromneuritinknock-out mice, suggesting that neuritin may be involved in activity-dependent axonal branching. Moreover,neuritinknock-out mice showed less-severe seizures in chemical kindling probably by reduced mossy fiber sprouting and/or increased seizure resistance. We found that inhibition of the fibroblast growth factor (FGF) receptor attenuated the neuritin-dependent axonal branching. FGF administration also increased branching in granule neurons, whereasneuritinknock-out mice did not show FGF-dependent axonal branching. In addition, FGF and neuritin treatment enhanced the recruitment of FGF receptors to the cell surface. These findings suggest that neuritin and FGF cooperate in inducing mossy fiber sprouting through FGF signaling. Together, these results suggest that FGF and neuritin-mediated axonal branch induction are involved in the aggravation of epilepsy.


CONCLUSIONS
This study reveals the molecular mechanism underlying mossy fiber sprouting. Mossy fiber sprouting is the aberrant axonal branching of granule neurons in the hippocampus, which is observed in patients with epilepsy. Excess amounts of neuritin, a protein upregulated by neural activity, promoted axonal branching in granule neurons. A deficiency of neuritin suppressed mossy fiber sprouting and resulted in mitigation of seizure severity. Neuritin and fibroblast growth factor (FGF) cooperated in stimulating FGF signaling and enhancing axonal branching. Neuritin is necessary for FGF-mediated recruitment of FGF receptors to the cell surface. The recruitment of FGF receptors would promote axonal branching. The discovery of this new mechanism should contribute to the development of novel antiepileptic drugs to inhibit axonal branching via neuritin-FGF signaling.
Synaptic Plasticity Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan, and shimada-td@igakuken.or.jp yamagata-kn@igakuken.or.jp.
Tadayuki
http://orcid.org/0000-0001-7333-9847
T
Shimada
Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
Tomoyuki
T
Yoshida
Synaptic Plasticity Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan, and shimada-td@igakuken.or.jp yamagata-kn@igakuken.or.jp.
Kanato
K
Yamagata
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000494:pharmacology / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; C484377:Nrn1 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors
axon; epilepsy; mossy fiber