As people age, it’s common to experience declines in cognitive functions such as spatial learning and memory. These declines are thought to be linked to changes in the brain, death of neurons, and decreased production rate of new neurons, in a process called adult neurogenesis. Adult neurogenesis occurs mainly in two brain regions in the mammalian brain. Among these two regions is the hippocampus, an area that is critical for spatial learning and memory. During hippocampal neurogenesis, radial glial like cells (RGLs) -the neural stem cells occupying the dentate gyrus of the hippocampus-, divide to give rise to new granular neurons which play important roles in spatial learning and memory. With aging, RGLs decrease leading to low production rate of new neurons. Gamma-aminobutyric acid (GABA), a well-known neurotransmitter, can enhance adult neurogenesis. The GABA effect is mediated by Cl¯ ions modulation, depending on the concentration gradient of Cl¯ ion inside the cell. In RGLs Cl¯ ions are high, due to the expression of sodium-potassium-chloride cotransporter 1 (NKCC1). NKCC1 pumps Cl¯ inside the cell and when GABA binds to its GABAA receptors, this would open the gates for Cl¯ efflux. The modulation in Cl¯ results in activating RGLs and induces their proliferation. In this study a transgenic NKCC1 knockout (NKCC1 KO) mouse model was used to investigate the impact of deleting NKCC1 from RGLs on adult neurogenesis and the related cognitive functions. Morris water maze and Contextual fear conditioning tests were used to assess spatial learning and memory. We found that NKCC1 KO in hippocampal RGLs reduces the flexibility of spatial learning in young mice and relatively impaired contextual discrimination in both young and middle-aged mice. The reason for this impairment is the decrease in adult neurogenesis. Voluntary running can enhance neurogenesis and compensate for the impairment in learning flexibility and contextual discrimination after NKCC1 KO in young mice.
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