Non-canonical mTOR-Independent Role of DEPDC5 in Regulating GABAergic Network Development

Mutations in DEPDC5 are causal factors for a broad spectrum of focal epilepsies, but the underlying pathogenic mechanisms are still largely unknown. To address this question, a zebrafish depdc5 knockout model showing spontaneous epileptiform events in the brain, increased drug-induced seizure susceptibility, general hypoactivity, premature death at 2-3 weeks post-fertilization, as well as the expected hyperactivation of mTOR signaling was developed. Using this model, the role of DEPDC5 in brain development was investigated using an unbiased whole-transcriptomic approach. Surprisingly, in addition to mTOR-associated genes, many genes involved in synaptic function, neurogenesis, axonogenesis, and GABA network activity were found to be dysregulated in larval brains. Although no gross defects in brain morphology or neuron loss were observed, immunostaining of depdc5-/- brains for several GABAergic markers revealed specific defects in the fine branching of the GABAergic network. Consistently, some defects in depdc5-/- could be compensated for by treatment with GABA, corroborating that GABA signaling is indeed involved in DEPDC5 pathogenicity. Further, the mTOR-independent nature of these neurodevelopmental defects was demonstrated by the inability of rapamycin to rescue the GABAergic network defects observed in depdc5-/- brains and, conversely, the inability of GABA to rescue the hypoactivity in another genetic model showing mTOR hyperactivation. This study hence provides the first in vivo evidence that DEPDC5 plays previously unknown roles apart from its canonical function as an mTOR inhibitor. Moreover, these results propose that defective neurodevelopment of GABAergic networks could be a key factor in epileptogenesis when DEPDC5 is mutated.

Jaar van publicatie:2018

BOF-keylabel:ja

IOF-keylabel:ja

BOF-publication weight:10

CSS-citation score:2

Auteurs:International

Authors from:Higher Education

Toegankelijkheid:Closed