Assistant Professor/Director Johns Hopkins School of Medicine Baltimore, Maryland, United States
Abstract: The balance of excitatory and inhibitory (E/I) neurons is essential for proper mammalian central nervous system (CNS) function, as disruptions in this balance are implicated in autism spectrum disorders (ASDs) and other neuropsychiatric conditions. For example, macrocephaly-associated autism is characterized by neural overgrowth resulting from excessive proliferation of FOXG1+ neural progenitor cells (NPCs), which skews the proportions of excitatory and inhibitory neurons. The development of the CNS requires precise regulation by intrinsic and extrinsic signaling molecules. A recent meta-analysis of autism trio/dyad exome sequences identified damaging mutations in components of the insulin-like growth factor 1 (IGF1) signaling pathway. IGF1, produced by endodermal support cells, plays a critical role in promoting the proliferation and maintenance of human neural precursor cells (hNPCs) through the mechanistic target of rapamycin (mTOR) pathway. This pathway regulates protein synthesis and cellular growth. Overexpression of IGF1 in the developing mouse brain leads to increased cortical volume without altering brain morphology; however, the neuronal composition of the expanded cortex has not been systematically explored. IGF1 signaling activates the PI3 kinase/AKT pathway, resulting in phosphorylation of the tuberous sclerosis complex (TSC), composed of TSC1 and TSC2 subunits, which in turn regulates mTOR activity. Ribosome profiling of hNPCs treated with the mTOR inhibitor Torin 1 identified 155 translational targets of mTOR signaling, including GSX1, a homeobox transcription factor essential for inhibitory neuron development. To investigate the role of mTOR-mediated regulation of GSX1, a GSX1-knockout human pluripotent stem cell line was generated. Additionally, human pluripotent stem cell lines with loss-of-function mutations in TSC1 or TSC2 were developed to phenotypically recapitulate tuberous sclerosis (TS), a syndromic form of autism associated with macrocephaly and decreased inhibitory neuron subtypes. Current and future studies aim to elucidate how mTOR-mediated regulation of GSX1 influences inhibitory neuron fate and contributes to the development of E/I balance, providing deeper insights into the molecular mechanisms underlying CNS disorders such as ASDs and TS.
Funding Source: NIH/NIA/Alzheimer's Disease Research Center Developmental Award (P30 AG066507)
