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 H₂R. Simultaneously, this effect is negatively regulated by presynaptic H₃R 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 H₂R 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 H₃R 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 H₂R and its downstream HCN2 channel in EPN^PV neurons and H₃R in EPN-projecting STN^Glu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

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