Project Summary/Abstract The axon initial segment (AIS) is a critical mediator of neuronal function, and changes in its structure or location have been implicated in several neurodegenerative conditions. In diseases such as diabetes and Alzheimer's disease, there is a shortening of the AIS with cognitive impairment. Dementia and mild cognitive impairment are well recognized comorbidities of type 2 diabetes, termed diabetic encephalopathy, that lack in course modifying treatment options. AIS shortening may be reversible, hence investigating the mechanism responsible could address this significant gap in patient care by providing new therapeutic targets. The overall goal of this proposal is to examine the cellular mechanisms responsible for AIS shortening in these patients while providing the training necessary to support the career development of the applicant. Endoplasmic reticulum (ER) stress, a cellular condition that activates the unfolded protein response (UPR) has been implicated in diabetic encephalopathy. Preliminary studies show induction of ER stress induces AIS shortening, and inhibition of ER stress prevents AIS shortening in vitro. This NRSA F30 proposal will test the hypothesis that endoplasmic reticulum stress modulates the axon initial segment leading to cognitive impairment in type 2 diabetes utilizing two aims. Aim 1 will test the hypothesis that the UPR PERK pathway underlies ER stress- induced AIS shortening. The PERK pathway of the UPR activates calcineurin, a phosphatase associated with AIS shortening. This aim will pharmacologically and genetically inhibit PERK in mouse cortical neuron culture and evaluate changes in AIS structure and neuronal network activity following ER stress induction. Aim 2 will test the hypothesis that ER stress inhibition ameliorates AIS shortening and cognitive impairment in diabetes. This aim will inhibit ER stress in db/db mice, an established model of type 2 diabetes, and evaluate changes in cognitive performance and AIS structure. Confirmation of the central hypothesis in the proposed study will identify ER stress and AIS shortening as therapeutic targets to mitigate cognitive impairment in diabetic encephalopathy. Completion of this proposal will also provide opportunities for training key to the applicant's future research goal to be an independent physician scientist studying changes in neural transmission and cognitive defects caused by neurodegenerative diseases. This proposal is significant because completion will elucidate a target for therapeutic research to treat this condition in patients with type 2 diabetes while training a future physician scientist who will care for them.