In healthy subjects, the excitable axonal domains known as the axon initial segment (AIS) and node of Ranvier (node) allow rapid, efficient, and regulated communication within the nervous system. Emerging evidence indicates that subtle disruption and/or plasticity of the structure-function relationship at these domains impairs neuronal function and is associated with a wide variety of neurological diseases. For example, Leo Yermakov, a MD/PhD candidate in the Susuki lab, recently published that type 2 diabetes leads to disruption of the AIS in the prefrontal cortex and hippocampal brain regions of mice . Our current goal is to determine how excitable axonal domains are disrupted in type 2 diabetes and whether this leads to maladaptive neuronal network function and impairment of cognitive behavior. A clue comes from a recent publication from Dr. Ryan Griggs, a postdoctoral researcher in the lab, which reports that the diabetes-related metabolite methylglyoxal may disrupt nodes via the calcium-dependent protease calpain . These publications form the basis of our current working hypothesis that activation of calpains by pathological elevation of methylglyoxal leads to disruption of both excitable axonal domains and brain function in diabetes and related neurodegenerative conditions.