Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system
Luciana Frick1, Maximiliano Rapanelli1, Eeman Abbasi1
1Department of Psychiatry, Yale University, New Haven, CT, United States.
Abstract:
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.
Insights
Histamine deficiency alters brain microglia in mice, impacting their structure and increasing inflammatory response. This suggests a link between histamine signaling and neuroimmune regulation in conditions like Tourette syndrome.
Area of Science:
- Neuroscience
- Immunology
- Neuroinflammation
Background:
- Microglia are key regulators of brain homeostasis and neuroinflammation.
- Abnormalities in microglia are linked to neuropsychiatric disorders such as Tourette syndrome and autism.
- Histamine (HA) acts as a neurotransmitter and immune modulator, with deficiency implicated in Tourette syndrome.
Purpose of the Study:
- To investigate the in vivo effects of histamine deficiency and H4 receptor stimulation on microglia.
- To explore the role of histamine in regulating microglial morphology and function.
Main Methods:
- Immunohistochemistry was used to analyze microglia in histidine decarboxylase (Hdc) knockout mice (lacking histamine) and wild-type mice treated with HA receptor agonists.
- Microglial morphology, including ramifications, and expression of IGF-1 were examined.
- The response of microglia to lipopolysaccharide (LPS) challenge was assessed.
Main Results:
- Chronic histamine deficiency in Hdc knockout mice reduced microglial ramifications in the striatum and hypothalamus.
- Histamine deficiency led to a particular reduction in microglia expressing IGF-1.
- Microglial response to LPS challenge was potentiated in Hdc knockout mice, indicating heightened inflammatory sensitivity.
Conclusions:
- Histamine, acting via the H4 receptor, regulates microglia in vivo.
- Histamine deficiency may predispose individuals to exaggerated inflammatory responses in the brain.
- Dysregulated histaminergic signaling could contribute to neuropsychiatric conditions by altering neuroimmune responses.
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