Tsc1 represses parvalbumin expression and fast-spiking properties in somatostatin lineage cortical interneurons

Ruchi Malik,Emily Ling-Lin Pai,Anna N Rubin,Daniel Vogt,Kartik Angara,April M Stafford,Vikaas S Sohal,Petros Minasi,John L Rubenstein

doi:10.1038/s41467-019-12962-4

Abstract

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis Complex (TSC) gene, Tsc1, which inhibits the mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. Milder intermediate phenotypes also occur when only one allele of Tsc1 is deleted. Notably, treatment of adult mice with rapamycin, which inhibits MTOR, reverses the phenotypes. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to TSC neuropsychiatric symptoms. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.

Highlights

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties
HAMARTIN and TUBERIN proteins dimerize to form a protein complex that inhibits the activity of the mammalian target of rapamycin (MTOR), a protein complex that is a rheostat for energy homeostasis and is an important regulator of protein translation[7]
We investigated the role of Tsc1/MTOR signaling in CIN cell programming

Summary

Introduction

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. Mechanisms regulating their diversity remain poorly understood. We show that conditional loss of the Tuberous Sclerosis Complex (TSC) gene, Tsc[1], which inhibits the mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. Milder intermediate phenotypes occur when only one allele of Tsc[1] is deleted. Treatment of adult mice with rapamycin, which inhibits MTOR, reverses the phenotypes These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to TSC neuropsychiatric symptoms. We propose that the choice between SST+ and PV+ cell programming is mediated in part by non-transcriptional processes, including cellular signaling events, suggesting a new avenue towards understanding these important cell types

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Conclusion