**8. Intracellular mechanisms affecting NMDA receptor function**

Selective intracellular signal transduction pathways, such as the AKT‐GSK3β pathway, at excitatory glutamatergic synapses regulate NMDA receptor functions, and are associated with high‐risk genes involved in schizophrenia. AKT, also known as protein kinase B, is a serine/threonine kinase involved in neuronal plasticity, migration, protein synthesis, and cell death [43, 44]. Glycogen synthase kinase 3β (GSK3β) is also a serine/threonine kinase that is downstream of AKT and upstream of beta‐catenin [45]. Moreover, GSK3β knockdown leads to a reduction in NMDA receptor current [46]. AKT phosphorylation is a negative regulator of GSK3β activity; similarly, GSK3β phosphorylation induces beta‐catenin degradation. High‐ risk genes such as DISC1, dysbindin and NRG1 are all modulators of the AKT‐GSK3β signal‐ ing pathway [34]. For instance, reduced DISC1 protein expression causes a decrease in AKT phosphorylation, and thus an increase in GSK3β activity [47]. In addition, reducing GSK3β activity can alleviate the behavioral impairments observed in DISC1 mouse models [48, 49]. These data suggest a link between high‐risk schizophrenia genes and intracellular pathways, such as the AKT‐GSK3B signaling pathway, that regulate neuronal plasticity. Theoretically, it can be assumed that the high‐risk schizophrenia genes would affect the AKT‐GSK3β sig‐ naling pathway, and thus cause NMDA receptor dysfunction, leading to aberrant neuronal systems that are responsible for the positive, negative, and cognitive symptoms observed in schizophrenia.
