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Background and Purpose Parvalbumin (PV)‐positive neurons are a type of neuron in the lateral globus pallidus (LGP) which plays an important role in motor control. The present study investigated the effect of histamine on LGPPV neurons and motor behaviour. Experimental Approach Histamine levels in LGP as well as its histaminergic innervation were determined through brain stimulation, microdialysis, anterograde tracing and immunostaining. Mechanisms of histamine action were detected by immunostaining, single‐cell qPCR, whole‐cell patch‐clamp recording, optogenetic stimulation and CRISPR/Cas9 gene‐editing techniques. The effect of histamine on motor behaviour was detected by animal behavioural tests. Key Results A direct histaminergic innervation in LGP from the tuberomammillary nucleus (TMN) and a histamine‐induced increase in the intrinsic excitability of LGPPV neurons were determined by pharmacological blockade or by genetic knockout of the histamine H1 receptor (H1R)‐coupled TWIK‐related potassium channel‐1 (TREK‐1) and the small‐conductance calcium‐activated potassium channel (SK3), as well as by activation or overexpression of the histamine H2 receptor (H2R)‐coupled hyperpolarization‐activated cyclic nucleotide‐gated channel (HCN2). Histamine negatively regulated the STN → LGPGlu transmission in LGPPV neurons via the histamine H3 receptor (H3R), whereas blockage or knockout of H3R increased the intrinsic excitability of LGPPV neurons. Conclusions and Implications Our results indicated that the endogenous histaminergic innervation in the LGP can bidirectionally promote motor control by increasing the intrinsic excitability of LGPPV neurons through postsynaptic H1R and H2R, albeit its action was negatively regulated by the presynaptic H3R, thereby suggesting possible role of histamine in motor deficits manifested in Parkinson's disease (PD).

In Parkinson’s disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide–gated (HCN) channels coupled to postsynaptic H 2 R. Simultaneously, this effect is negatively regulated by presynaptic H 3 R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H 2 R or genetic upregulation of HCN2 in EPN PV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPN PV neurons and pharmacological activation or genetic upregulation of H 3 R in EPN-projecting STN Glu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPN PV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPN PV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H 2 R and its downstream HCN2 channel in EPN PV neurons and H 3 R in EPN-projecting STN Glu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.