"MTOR and cortical GABAergic interneuron development: new insights"
Excitatory and inhibitory neurons operate in tandem for proper brain function but in many cases their balance is disrupted, which may underlie symptoms of neuropsychiatric disorders. In particular, GABAergic cortical interneurons (CINs) are a primary source of inhibition and provide this in many ways through a diverse population of unique CIN types with divergent molecular, cellular and physiological properties. The underlying mechanisms that promote their unique properties are a matter of intense study and the developmental biology of one type specifically, fast-spiking CINs that express parvalbumin (PV), is the least understood. For many decades we have focused on transcription factors as the primary determinants of CIN properties but have not looked extensively at other processes like cellular signaling. Herein, we examined the consequences of deleting the syndromic gene, Tsc1, which underlies Tuberous Sclerosis Complex, to uncover its role in CIN development. Tsc1 is part of a well-studied signaling pathway that inhibits mammalian target of rapamycin (MTOR), which positively regulates cell growth and survival. Unexpectedly, we found that a small group of CINs that normally express somatostatin aberrantly expressed PV and exhibited fast-spiking properties when Tsc1 was depleted. These phenotypes were cell autonomous and could be rescued by the MTOR inhibitor rapamycin at adult ages, suggesting that the ability to upregulate PV expression and fast-spiking properties could be modulated by cellular signaling events and was dynamic in adult mice. This presents a new inroad into how some CIN properties may arise, not only by transcriptional programming but also events outside the nucleus coming into play.