Martina Proietti OnoriID1,2, Linda M. C. KoeneID1,2☯, Carmen B. Scha¨fer1☯, Mark Nellist3
Marcel de Brito van VelzeID1
, Zhenyu Gao1
, Ype ElgersmaID1,2,3*, Geeske M. van
1 Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands, 2 The ENCORE
Expertise Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, the Netherlands,
3 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Zuid Holland, the Netherlands
Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.
Full-field optogenetic stimulation (470 nm peak excitation) was generated by the use of a TTL-pulse controlled pE2 light emitting diode (CoolLED, Andover, UK).
Product Associated Features
The pE-2 was one of the first highly controllable LED Illumination Systems available to offer wavelength flexibility, including 470 nm. The single-band pE-100 470 nm is now a popular solution for optogenetic stimulation in highly controllable pulses.
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South Korea, The Netherlands