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Brain Behav Immun. 2016 Oct;57:326-337. doi: 10.1016/j.bbi.2016.07.002. Epub 2016 Jul 2.

Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation.

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Department of Psychiatry, Yale University, New Haven, CT, United States.
Tohoku University, Graduate School of Engineering, Sendai, Japan.
Department of Psychiatry, Yale University, New Haven, CT, United States; Department of Psychology, Yale University, New Haven, CT, United States; Child Study Center, Yale University, New Haven, CT, United States; Interdepartmental Neuroscience Program, Yale University, New Haven, CT, United States. Electronic address:


Microglia mediate neuroinflammation and regulate brain development and homeostasis. Microglial abnormalities are implicated in a range of neuropsychiatric pathology, including Tourette syndrome (TS) and autism. Histamine (HA) is both a neurotransmitter and an immune modulator. HA deficiency has been implicated as a rare cause of TS and may contribute to other neuropsychiatric conditions. In vitro studies suggest that HA can regulate microglia, but this has never been explored in vivo. We used immunohistochemistry to examine the effects of HA deficiency in histidine decarboxylase (Hdc) knockout mice and of HA receptor stimulation in wild-type animals. We find HA to regulate microglia in vivo, via the H4 receptor. Chronic HA deficiency in Hdc knockout mice reduces ramifications of microglia in the striatum and (at trend level) in the hypothalamus, but not elsewhere in the brain. Depletion of histaminergic neurons in the hypothalamus has a similar effect. Microglia expressing IGF-1 are particularly reduced, However, the microglial response to challenge with lipopolysacchariade (LPS) is potentiated in Hdc knockout mice. Genetic abnormalities in histaminergic signaling may produce a vulnerability to inflammatory challenge, setting the state for pathogenically dysregulated neuroimmune responses.


Basal ganglia; H4R receptor; IGF-1; Lipopolysaccharide

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