Chronic Neurobehavioral Impairments and Decreased Hippocampal Expression of Genes Important for Brain Glucose Utilization in a Mouse Model of Mild TBI.

Abstract

Glucose is an essential cellular fuel for maintaining normal brain functions. Traumatic brain injury (TBI) decreases brain glucose utilization in both human and experimental animals during the acute or subacute phase of TBI. It remains unclear as to how the damages affect brain glucose utilization and its association with persistent neurobehavioral impairments in the chronic phase of mild TBI (mTBI). Accordingly, we compared expression of selected genes important to brain glucose utilization in different brain regions of mice during the chronic phase in mTBI vs. sham operated mice. These genes included hexokinase-1 (HK1), phosphofructokinase (PFK), pyruvate kinase (PK), pyruvate dehydrogenase (PDH), capillary glucose transporter (Glut-1), neuron glucose transporter (Glut-3), astrocyte lactate transpor1 (MCT-1), neuron lactate transporter (MCT-2), lactate receptor (GPR81), and Hexokinase isoform-2 (HK2). Young adult male C57BL/6J mice were brain injured with repetitive closed-head concussions. Morris water maze (MWM), elevated plus maze (EPM), and neurological severity score test (NSS) were performed for evaluation of mice neurobehavioral impairments at 2, 4, and 6 months post mTBI. Two days after completion of the last behavioral test, the frontal cortex, hippocampus, brainstem, hypothalamus, and cerebellum were collected for gene expression measurements. The expression of the mRNAs encoding PK, and PDH, two critical enzymes in glucose metabolism, was decreased at all-time points only in the hippocampus, but was unchanged in the brainstem, hypothalamus, and cortex in mTBI mice. mTBI mice also exhibited the following behavioral alterations: (1) decreased spatial learning and memory 2, 4, and 6 months after the injury, (2) increased proportion of time spent on open vs. closed arms determined by EPM, and (3) accelerated reduction in motor activity observed at 4 months, two months earlier than observed in the sham group, during the EPM testing. There were no significant differences in NSS between injury and sham groups at any of the three time points. Thus, mTBI in male mice led to persistent decreased hippocampal expression of mRNAs that encode critical glucose utilization related enzymes in association with long-term impairments in selected neurobehavioral outcomes.