SAT043 Chronically High Cerebrospinal Fluid Glucose Levels Impair Memory In Male Mice

Disclosure: M.U. Raza: None. K.H. Chhabra: None. Diabetes doubles the risk of cognitive decline and Alzheimer’s disease (AD). Whether this is mediated by an increase in blood glucose or cerebrospinal fluid (CSF) glucose levels, or by other metabolic factors such as changes in plasma insulin levels is unclear. To clarify the contribution of high blood glucose versus high CSF glucose levels toward increasing the risk of cognitive decline in mice, we have developed a method through which glucose concentration can be increased selectively in CSF. We implanted 8 weeks old male mice (n= 7-8 / group) with cannula attached to osmotic minipumps to directly infuse either artificial CSF (aCSF/sham group) or 50% glucose solution (treatment group) into the right lateral ventricle for eight weeks at a flow rate of 0.25ul/hr. CSF glucose was measured two and eight weeks after initiating the infusion in these mice. We also performed oral glucose tolerance tests (OGTT) in these mice to assess their peripheral glucose metabolism and uptake. Moreover, these mice were tested through the Morris water maze (MWM) to investigate the effects of high CSF glucose on learning and memory. Mice in the treatment group showed a significant increase (p<0.0001, unpaired t-test) in CSF glucose levels (mean=328±30.15 and 358±15.03mg/dl post-2, and 8 weeks of implantation, respectively) as compared to the sham group (mean=56±2.63 and 73±8.61mg/dl post-2, and 8 weeks of implantation, respectively). There was no significant change in body weight and food intake during the study. In OGTT, the treatment group showed significantly lower blood glucose levels (p<0.05, two-way ANOVA repeated measures design, Bonferroni’s multiple comparisons) at 15 minutes post-gavage (mean=336.3±24.41mg/dl) as compared to the sham group (mean=478.6±30.06 mg/dl). Mice in the treatment group made significantly fewer entries to the correct quadrant (i.e. the quadrant where the hidden platform was placed during training) (mean=12.43±1.55 entries, p<0.05, unpaired t-test) in the MWM test, as compared to the sham group (mean=18.4±1.84 entries). Additionally, mice in the treatment group were significantly less likely to revisit the correct quadrant (mean=10.7±1.50 revisits, p<0.05, unpaired t-test) than the mice in the sham group (mean=16.8±1.78 revisits). Importantly, there was no significant difference in the overall locomotor activity between the groups as measured through the open field test. To summarize, we have developed a method to test the effects of high CSF glucose levels on learning and memory in mice. Our results show that high CSF glucose levels for up to two months cause memory deficits in mice. This mouse model of chronically high CSF glucose presents a useful tool to investigate how diabetes-associated dysregulation of glucose homeostasis in the brain may contribute to AD and other neurodegenerative disorders. Presentation: Saturday, June 17, 2023