Abstract
Calstabin2, also named FK506 binding protein 12.6 (FKBP12.6), is a subunit of ryanodine receptor subtype 2 (RyR2) macromolecular complex, which is an intracellular calcium channel and abundant in the brain. Previous studies identified a role of leaky neuronal RyR2 in posttraumatic stress disorder (PTSD). However, the functional role of Calstabin2 in the cognitive function remains unclear. Herein, we used a mouse model of genetic deletion of Calstabin2 to investigate the function of Calstabin2 in cognitive dysfunction. We found that Calstabin2 knockout (KO) mice showed significantly reduced performance in Morris Water Maze (MWM), long-term memory (LTM) contextual fear testing, and rotarod test when compared to wild type (WT) littermates. Indeed, genetic deletion of Calstabin2 reduced long-term potentiation (LTP) at the hippocampal CA3-CA1 connection, increased membrane excitability, and induced RyR2 leak. Finally, we demonstrated that the increase in cytoplasmic calcium activated Ca2+ dependent potassium currents and led to neuronal apoptosis in KO hippocampal neurons. Thus, these results suggest that neuronal RyR2 Ca2+ leak due to Calstabin2 deletion contributes to learning deficiency and memory impairment.
Highlights
Mice during the probe trial session in the water Morris maze. (C) Quadrant preference of mice during the 1 min probe at day 10
Intracellular calcium (Ca2+ ) homeostasis plays a crucial role in regulating neurological processes including synaptic transmission, secretion, excitability, learning, and memory[29]
It has been reported that elevated intracellular Ca2+ is associated with cognitive dysfunction due to brain injury and neurodegeneration[35,36]
Summary
Mice during the probe trial session in the water Morris maze. (C) Quadrant preference of mice during the 1 min probe at day 10. Calstabin[2] deletion significantly affected quadrant preference in KO mice. It has been reported that Calstabin[1] (FKBP12), which shares 85% sequence identity with Calstabin[2], regulates mTOR-Raptor interactions through binding of rapamycin and inhibiting the activity of the mammalian target of rapamycin (mTOR), a key regulator of aging[23]. Through this pathway, Calstabin[2] can affect long-term potentiation (LTP), memory, and perseverative behaviors[10]. Following RyR2-mediated calcium leak, intracellular Ca2+ homeostasis is disturbed and Ca2+ dependent potassium currents are activated, signaling downstream apoptotic pathways and resulting in hippocampal neuron death
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