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bioRxiv · 10.1101/777714

Enhanced maturation of fast-spiking interneurons driven by mTOR activation

Chu, J.·Fitzgerald, M. L.·Sehgal, N.·Manley, W.·Fitzgerald, S.·Naung, H.·Goldberg, E. M.·Anderson, S. A.
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Abstract

The use of stem cell derived neurons for cell-based therapies is limited by a protracted maturation. We present a novel approach for accelerating the post-mitotic maturation of human stem cell derived interneurons via the activation of mTOR signaling. Lox sites were placed within PTEN, a key mTOR inhibitor, in a cortical interneuron (CIn) reporter line. Following directed differentiation and purification by FACS, the CIns were exposed to Cre-expressing lentivirus, then transplanted into mouse neocortex or plated onto cultured rat neocortex. Input synaptogenesis and dendritogenesis was greatly enhanced in the PTEN-deleted CIns. Whole-cell recording of the PTEN-deleted CIns in slices of transplanted neocortex revealed multiple indices of enhanced maturation. Finally, we observed similar effects using transient, doxycycline-inducible activation of AKT. We thus present an inducible, reversible approach for accelerating the maturation of human stem cell derived CIns, and to study the influences of this disease-related signaling system in human neurons.

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Chu, J., Fitzgerald, M. L., Sehgal, N., Manley, W., Fitzgerald, S., Naung, H., Goldberg, E. M., Anderson, S. A.. 2019-09-20. Enhanced maturation of fast-spiking interneurons driven by mTOR activation. https://doi.org/10.1101/777714

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