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

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.

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

“…We have described complex abnormalities of microglia in a mouse model of Tourette syndrome [46]. Naïve Hdc-KO mice display morphological abnormalities in striatal microglia that suggest quiescence, normal expression of inflammatory markers, but a reduced number of IGF-1 expressing microglia.…”

“…We found that microglia cells are not activated in basal conditions in the striatum in Hdc -KO mice; rather, microglia from this mice exhibit reduced arborization and normal expression of inflammatory markers [46]. A similar effect is seen when neuronally derived histamine is specifically disrupted, through targeted virus-mediated ablation of histaminergic neurons in the posterior hypothalamus [46]. The total number of microglia is unchanged in KO animals, but the number of microglia expressing Insulin-like Growth Factor 1 (IGF-1) is reduced.…”

“…The normal number of microglia in the Hdc -KO model and their reduced arborization at baseline [46] contrast with the more numerous and activated microglia seen postmortem [39]. It is possible that the activation of microglia observed in patients with Tourette syndrome emerges only after challenge by environmental factors, such as infection, or over the course of aging.…”

“…It is possible that the activation of microglia observed in patients with Tourette syndrome emerges only after challenge by environmental factors, such as infection, or over the course of aging. Our studies in mice [44, 46] are performed in a pathogen-free environment, in young adult mice. After LPS challenge, microglia activation in the animal model much more closely resembles that seen postmortem in humans.…”

“…After LPS challenge, microglia activation in the animal model much more closely resembles that seen postmortem in humans. Regardless of this consideration, all the studies point to activation of microglia in the basal ganglia in Tourette syndrome [39, 41, 46], irrespective of the complexity of the underlying mechanisms.…”