Histamine and deep brain stimulation: the pharmacology of regularizing a brain

Abstract

Parkinson's disease (PD) patients have increased histamine in their basal ganglia, but the role of this neurotransmitter in PD is poorly understood. In this issue of the JCI, Zhuang et al. demonstrate that histamine levels rise in the subthalamic nucleus (STN) to compensate for abnormal firing patterns. Injection of histamine into the STN restores normal firing patterns and motor activity, whereas merely changing firing rates has no behavioral effect. Moreover, STN deep brain stimulation, a widespread therapy for PD, regularizes firing through endogenous histamine release. This suggests that abnormal firing patterns, rather than rates, cause PD symptoms, and this histaminergic pathway may lead to new treatments for the disease.

Figure 1. A model of Zhuang et al.’s proposed STN regularization mechanism.

(A) An STN neuron in a Parkinsonian brain fires an irregular spike train due to downregulation of HCN channels. (B) DBS evokes endogenous histamine release. Histamine binds to H2 receptors coupled to HCN channels, which allows them to open, thereby regularizing the STN neuron’s spike train.