(A) Indicated are the 5 SNPs within the AKT1 locus that were examined by Emamian et al. (2), as well as by Tan et al. in their current study in this issue of the JCI (16). The rs1130233 SNP that reduces expression of AKT1 appears in red. AKT1 has 16 exons (boxes). Coding sequence (blue boxes) flanked by the start (ATG) and stop (TGA) codons as well as expressed noncoding sequence (white boxes) are indicated. (B) AKT is a key node for various signaling systems. DA in the cortex is inactivated by COMT and activates DRD1-coupled cAMP signaling whereas DRD2 decreases cAMP levels and inhibits AKT activity via β-arrestin2. GABA, glutamate (GLU), and various growth factors (GFs) also modulate AKT activity via PI3K, resulting in alterations in synaptic growth and transmission. (C) These combined effects on DA modulation and synaptic connectivity may alter the function of cells (circles) within neuronal circuits important for cognitive function. The caudate of the basal ganglia plays a critical role in gating information and restricting access to working memory, which relies on proper connections among cortical neurons in the PFC. The gating of information itself is heavily dependent on DA transmission, which originates from the ventral tegmental area (VTA). One possible, although probably oversimplified, scenario is that sensitization to DA via DRD2 may lead to psychotic symptoms and, coupled with altered neuronal connectivity and decreased DRD1 signaling, also contribute to cognitive dysfunction. Dashed lines represent the functional impairments resulting from the SNP4-dependent attenuation of AKT1 expression and signaling.