In line with the transcriptome changes, we found biased production of neuronal subtypes from cortical neuron precursors of ASD probands, as compared with their fathers. Cortical organoids of ASD probands show, at all time points analyzed, exuberant GABAergic differentiation and no change in glutamate neuron types, which together cause an imbalance in glutamate/GABA neuron ratio. Interestingly, an unbiased stereological study in postmortem human samples showed an increase in three GABA interneuron subtypes in various subregions of the hippocampus in ASD, albeit in a small number of patients (Lawrence et al., 2010). We also found that the overproduction of GABAergic cells is attributable, at least in part, to an early increase in FOXG1 gene expression, which drives an increased proliferation and number of GABA precursor cells expressing TF driving GABAergic neuron fates, including the DLX homeobox genes (Rubenstein, 2010). FOXG1 inactivation in mice causes premature lengthening of telencephalic progenitor cell cycles and a failure to specify ventral (GABAergic) telencephalic precursors, leading to a severely hypoplastic telencephalon (Fasano et al., 2009; Martynoga et al., 2005). Hence, our data in humans are consistent with the known roles of FOXG1 in telencephalic growth as well as in the determination of GABA neuron fate.
