Studies of rare exonic mutations have suggested that genes expressed during early fetal cortical development are etiologically implicated in ASD 134,135. In an effort to directly model early cortical development of patients with idiopathic autism, we produced hiPSC-derived telencephalic organoids from the fibroblasts of ASD patients with macrocephaly. The telencephalon is the embryonic structure that gives rise to the cerebral cortex, hippocampus, basal ganglia, and olfactory bulb. The ventral telencephalon gives rise to the basal ganglia, the principal source of cortical inhibitory interneurons, while the dorsal telencephalon gives rise to the excitatory projection neurons of the cerebral cortex. Telencephalic organoids contain both glutamatergic (excitatory) cortical neurons and GABAergic (inhibitory) cortical neurons. Macrocephaly refers to an increased head circumference due to increased brain size, and is one of the most consistently replicated phenotypes in ASD 136–138. Furthermore, ASD patients who present with macrocephaly usually have more severe symptoms and poorer outcomes. In this study, organoids were used to reflect early to mid-fetal telencephalic development in humans.
