Abstract P030: Early Cognitive Deficits Induced by Diabetes Are Masked by an Increase in Exploratory Behavior: Evidence From TLR2 Knock-out Mice

Abstract

Toll-like receptor 2 (TLR2) has been shown to contribute to cardiovascular complications of diabetes such as nephropathy. However, the role of TLR2 in cerebrovascular inflammation and dysfunction leading to cognitive impairment, an emerging cerebrovascular complication of diabetes and hypertension, remains unknown. We reported that streptozotocin (STZ)-induced type-1 diabetic TLR2 knockout mice were protected from decreased cerebral blood flow (CBF) at 4 and 6 weeks post induction. Given that decreased CBF precedes cognitive impairment, we hypothesized that these TLR2-KO STZ mice would subsequently be protected from cognitive impairment. 10 week old male C57Bl:6 and TLR2-KO mice were injected with 50mg STZ/kg body weight daily for 5 days and observed alongside control mice. Fasting blood glucose was measured, with levels > 240 mg/dL considered to confirm diabetes. Cognitive function was assessed via Y-maze testing. There was no difference in total arm entries between WT and WT-STZ mice or between WT and TLR2-KO. There was a significant decrease in total entries between TLR2-KO and TLR2-KO STZ (40.33± 1.88 vs.29.67± 2.09, p≥0.05, n=12/group). However, percent novel arm entries was statistically non-significant amongst all groups. Paradoxically, both diabetic groups had a non-significant increase in percent of time spent in the novel arm vs. their respective controls (WT-STZ: 35.7±5.3 seconds vs. WT: 33.2± 4.4 seconds; TLR2-KO STZ: 41.6±5.8 seconds vs. TLR2-KO: 37.9±5.5 seconds). The lack of difference in percent novel arm entries is likely a result of the relative increase in exploratory behavior in the STZ groups. Additional experiments with open-field testing and novel object recognition test are being performed to determine if the apparent lack of change in short term hippocampal memory is due to a confounding artifact of the exploration time and whether these cognitive tests are accompanied by changes in CBF in this cohort. If indeed TLR2 KO mice are protected from early mild cognitive deficits, TLR2 antagonism may be a novel target in the prevention/treatment of cerebrovascular complications of diabetes.