Histamine Excites Striatal Dopamine D1 and D2 Receptor-Expressing Neurons via Postsynaptic H1 and H2 Receptors

Abstract

The central histaminergic nervous system, originating from the tuberomammillary nucleus (TMN) of the hypothalamus, widely innervates almost the whole brain, including the basal ganglia. Intriguingly, the histaminergic system is altered in parkinsonian patients. Yet, little is known about the effect and mechanisms of histamine on different types of neurons in the basal ganglia circuitry. Here, by using anterograde tracing, immunostaining, patch clamp recording, and single-cell qPCR techniques, we investigate the histaminergic afferents in the striatum, the major input structure of the basal ganglia, as well as the effect of histamine on the striatal GABAergic medium spiny projection neurons (MSNs). We report a direct histaminergic projection from the hypothalamic TMN to the striatum in rats. Furthermore, histamine exerts a strong postsynaptic excitatory effect on both dopamine D1 and D2 receptor-expressing MSNs. The concentration-response curves and the EC values for histamine on these two types of MSNs are similar. In addition, dopamine D1 and D2 receptor-expressing MSNs co-express histamine H1 and H2 receptor mRNAs. Both histamine H1 and H2 receptors are co-localized on dopamine D1 and D2 receptor-expressing MSNs and co-mediate the histamine-induced excitation on the two types of neurons. These results suggest that the histaminergic afferent inputs in the striatum may modulate both dopamine D1 and D2 receptor-expressing MSNs by activation of postsynaptic histamine H1 and H2 receptors and thus serve as an important extrastriatal modulator for biasing the direct and indirect pathways to actively regulate functions of the basal ganglia and participate in the pathogenesis and pathophysiology of basal ganglia diseases.

Impaired Cortical Cytoarchitecture and Reduced Excitability of Deep-Layer Neurons in the Offspring of Diabetic Rats

“…The increase in action potential frequency promoted by histamine in deep-layer cortical neurons is in accordance with the increased excitability previously reported for neurons in other regions of the CNS, namely thalamus (McCormick and Williamson, 1991), layer 6b of the primary somatosensory cortex (Wenger Combremont et al, 2016), entorhinal cortex (Cilz and Lei, 2017), ventral pallidum (Ji et al, 2018), striatum (Zhuang et al, 2018), and spinal cord (Wu et al, 2019). Furthermore, the lack of difference in H 1 R density supports that the electrophysiological changes observed in the offspring of diabetic rats rely mainly on morphological alterations.…”

“…In several brain nuclei histamine increases neuronal excitability through a dual-action mediated by H 1 and H 2 receptors (see for instance McCormick and Williamson, 1991;Ji et al, 2018;Zhuang et al, 2018). The H 1 R-mediated excitatory effect involves a mixed ionic mechanism, namely closing of K + channels, activation of Na + channels and stimulation of the Na + -Ca 2+ exchanger (McCormick and Williamson, 1991;Cilz and Lei, 2017;Wu et al, 2019).…”

Abnormal behavior, striatal dopamine turnover and opioid peptide gene expression in histamine‐deficient mice

“…There is a large body of evidence from in‐vitro studies and in vivo studies on Hdc and Hrh3 KO mice that Hrh3 regulates striatal activity . In addition, Hrh1 and Hrh2 are also present on the soma of MSN and other striatal cells and could contribute to adjusting MSN level of activity …”

“…7,10,[46][47][48] In addition, Hrh1 and Hrh2 are also present on the soma of MSN and other striatal cells and could contribute to adjusting MSN level of activity. 49 Given these data and studies that have shown regulation of striatal opioids by Hrh3, we hypothesized that striatal opioid systems might be altered in Hdc KO mice and analyzed gene expression of dynorphin and enkephalin. We found decreased dynorphin and enkephalin expression in the striatum of Hdc KO mice.…”

Central Effects of 3-Iodothyronamine Reveal a Novel Role for Mitochondrial Monoamine Oxidases

“…Interestingly enough, in the striatum, the main MAO isoform expressed is type B, which is the enzyme involved in T1AM (but also dopamine) degradation ( 20 ). Furthermore, other recent evidence also indicates that the release of dopamine in the striatum may be controlled by histamine released from the tuberomammillary nucleus, via H1 and H2 receptors ( 38 ). Overall, these results suggest T1AM might sustain dopamine synthesis and release acting at high-affinity targets (TAARs) and, indirectly, releasing histamine from the hypothalamic neurons.…”