BRAIN RESIDENT MAST CELLS REGULATE BRAIN HISTAMINE CONTENT AND PROMOTE WAKEFULNESS

Mast cells release various chemical mediators such as histamine and cytokines and play a central role in acute allergic reaction in peripheral organs. Recent studies showed some contributions of brain resident mast cells to brain histamine content and neurological functions. Our previous study demonstrated that wake-promoting effect by a histamine releaser was abolished in congenital mast cell deficient W/Wv mice (i.e., c-kit mutant mice). However, it is known that the mutant mice have multiple organ abnormalities beside mast cell deficiency. Here, we examined the roles of brain-resident mast cells in sleep/wake regulations using inducible mast cell and basophil deficient mice. Mas-TRECK (MT) mice express diphtheria toxin receptors specifically in mast cells and basophils, while Bas-TRECK (BT) mice in only basophils. Toxin treatment systemically and exclusively deletes mast cells or basophils in these mice but not wild-type mice. Adult male mice underwent surgery for EEG/EMG electrodes and E-mitters. Sleep phenotype was characterized at 5 and 30 days after toxin injection. The amount of monoamines and histamine in the whole brain was measured sequentially. A battery of behavioral assays was performed to evaluate their neurobehaviors. In MT mice, whole brain histamine contents dramatically decreased to less than half at 1 week after toxin injection, followed by a gradual recovery to the original level by 45 days. There was no change in the monoamine contents. One the other hand, BT mice showed no change in the histamine level. MT mice exhibited the decreased amount of arousal during light period at 1 week, while no significant difference in sleep-wake cycle was observed compared to the wild-type mice at 30 days. BT mice did not show any sleep changes by the loss of basophils. There was no marked change in neurological functions in terms of anxiety, depression, motor coordination, and recognition memory. Our findings demonstrate that brain resident mast cells serve as a major pool of brain histamine and contribute to the maintenance of sleep/wake regulation. It is warranted to determine how brain mast cells promote wakefulness. Support (If Any)