Neural Stem Cell Fatty Acid Beta‐Oxidation and Autism Spectrum Disease

Abstract

Inborn errors of metabolism occur with high incidence in human populations, and inborn deficiencies in fatty acid b‐oxidation (FAO) are clinically associated with neurological deficits such as speech weakness, motor delay, and autism. Using in vivo assays for analyzing neural stem cells (NSCs) in the developing mammalian forebrain, we find that neural stem cell (NSC)‐autonomous deficiencies in long‐chain FAO deplete neural stem cell (NSC) pools from mouse embryonic neocortex. Acute interference with activity of TMLHE (catalyzes the first step in carnitine biosynthesis), or with CPT1A (the rate‐limiting enzyme for carnitine‐dependent transport of long‐chain fatty acids into mitochondria), results in impaired NSC self‐renewal. Moreover, dorsal forebrain‐specific eviction of the Cpt1a gene resulted in reduced thickness of the murine neocortex at birth. Importantly, NSC deficits induced by TMLHE insufficiencies are rescued by exogenous carnitine in both cultured explants and by supplementation of the maternal diet. Taken together, the data argue for a direct role for FAO in controlling NSC self‐renewal vs differentiation in mammalian embryonic brain. The data further argue that deranged stem cell homeostasis is a significant mechanism for linking IEMs with human cognitive disorders such as autism. The implications of these findings for new strategies for management of autism risk will be discussed.Support or Funding InformationThis work was supported by the Robert A. Welch Foundation Award BE0017 and grant RO1GM112591 from the National Institute of HealthThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.