Reduced Hippocampal Neuronal Activity and Impaired Cognitive Function in a Mouse Model of Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is characterized by a progressive loss of renal function that leads to an accumulation of uremic toxins in the circulation, despite regular dialysis. In CKD, uremic toxins can cross the blood‐brain barrier and cause neuroinflammation. Consequently, patients with CKD experience various symptoms, including fatigue and impaired cognitive function. A significant barrier to investigation of uremic toxicity and its impact on cognitive function has been the difficulty of performing studies in humans, due in part to the lack of access to relevant tissues. To examine the pathogenic mechanism of uremic toxicity in the development of cognitive impairments, a partial nephrectomy (PNx) mouse model was used as the experimental system. Sham and PNx mice were maintained for 12‐14 weeks after 5/6 nephrectomy and then assessed for motor function, cognitive function, and neuronal activity. Kidney function, as measured by glomerular filtration rate, was reduced by 40% in PNx mice, which corresponded to a 65% reduction in kidney mass. Blood urea nitrogen levels were 2.3 times higher in PNx mice, but no significant changes in plasma creatinine levels were observed. Despite reduced kidney function, PNx mice performed at the same level as sham controls in ambulatory activity, working spatial memory, and object recognition. There was also no evidence of increased anxiety. However, in the Puzzle Box paradigm, in which mice were tested for problem solving skills over multiple days with increasingly difficult tasks, PNx mice on average took three times longer to overcome the obstacle in the final two tasks. Ex vivo examination of neuronal activity following exposure to a novel environment revealed a 30% reduction in c‐Fos positive neurons in the hippocampal dentate gyrus in PNx mice. Similarly, the population of fast‐spiking parvalbumin positive interneurons, which are essential for coordinating neuronal activities, were also reduced in PNx mice. Collectively, the data support a correlation between reduced neuronal activity and impaired cognitive performance in PNx mice. These impairments are likely a consequence of exposure to elevated levels of uremic toxins in the brain due to reduced kidney function.