Hyeuk Cha # 1 2, Jun Ho Choi # 1, Hanwool Jeon # 1 3, Jae Hyun Kim 1, Moinay Kim 1, Su Jung Kim 4, Wonhyoung Park 1 5, Joon Seo Lim 6, Eunyeup Lee 1 2, Jae Sung Ahn 1 5, Jeong Hoon Kim 1 5, Seok Ho Hong 1 5, Ji Eun Park 5 7, Jin Hwa Jung 4, Hyun Ju Yoo 5 4, Seungjoo Lee 8 9 10 11
Abstract
Cognitive impairment refers to notable declines in cognitive abilities including memory, language, and emotional stability leading to the inability to accomplish essential activities of daily living. Astrocytes play an important role in cognitive function, and homeostasis of the astrocyte-neuron lactate shuttle (ANLS) system is essential for maintaining cognitive functions. Aquaporin-4 (AQP-4) is a water channel expressed in astrocytes and has been shown to be associated with various brain disorders, but the direct relationship between learning, memory, and AQP-4 is unclear. We examined the relationship between AQP-4 and cognitive functions related to learning and memory. Mice with genetic deletion of AQP-4 showed significant behavioral and emotional changes including hyperactivity and instability, and impaired cognitive functions such as spatial learning and memory retention. 18 F-FDG PET imaging showed significant metabolic changes in the brains of AQP-4 knockout mice such as reductions in glucose absorption. Such metabolic changes in the brain seemed to be the direct results of changes in the expression of metabolite transporters, as the mRNA levels of multiple glucose and lactate transporters in astrocytes and neurons were significantly decreased in the cortex and hippocampus of AQP-4 knockout mice. Indeed, AQP-4 knockout mice showed significantly higher accumulation of both glucose and lactate in their brains compared with wild-type mice. Our results show that the deficiency of AQP-4 can cause problems in the metabolic function of astrocytes and lead to cognitive impairment, and that the deficiency of AQP4 in astrocyte endfeet can cause abnormalities in the ANLS system.
Keywords: Aquaporin-4; Astrocyte-neuron lactate shuttle; Cognitive impairment.
Reduced learning and cognitive abilities in AQP-4 KO mice
(A) Schematic representation of the Barnes maze test. (B,C) Escape latency and success rate of WT mice (black lines) and AQP-4 KO mice (red lines). (D) Representative traces of WT and AQP-4 KO mice during the first probe trial on day 5. (E.F): Short-term escape latency of WT mice (black lines) and AQP-4 KO mice (red lines). (G) Representative traces of WT and AQP-4 mice during the second probe trial on day 14. (H,I) Long-term escape latency of WT mice (black lines) and AQP-4 KO mice (red lines). Values are expressed as mean ± SEM (N per group = 7).(*P < 0.05, P < 0.01, *P < 0.001; two-way ANOVA)
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