This study not only represents a significant advance in understanding the neurobiological mechanisms underlying the N40D MOR variant in a human neuronal context, but also highlight the benefits of using human cell reprograming technology for in depth analysis of gene variants that have been associated with certain human disease. With our model we were able to generate homogeneous iN lines with MOR expression comparable to human thalamus. Currently we have not examined the effect of DAMGO on excitatory postsynaptic current (EPSC) frequency in other human neuronal subtypes. However, we hypothesize that NGN2 excitatory iN cells will likely exhibit a DAMGO mediated suppression of EPSC frequency assuming they express OPRM1. Whether or not the genotype-specific effect is observed in excitatory iN cells or whether it is characteristic to the inhibitory neuronal subtype can only be determined experimentally. However, considering our interest in understanding the role of N40D in inhibitory neurons that mimic those in the reward circuitry, characterizing the role of N40D in other neuronal subtypes will need further investigation.
