Histamine bidirectionally regulates the intrinsic excitability of parvalbumin-positive neurons in the lateral globus pallidus and promotes motor behaviour.

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 LGP 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 LGP neurons were determined by pharmacological blockade or by genetic knockout of the histamine H receptor (H R)-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 H receptor (H R)-coupled hyperpolarization-activated cyclic nucleotide-gated channel (HCN2). Histamine negatively regulated the STN → LGP transmission in LGP neurons via the histamine H receptor (H R), whereas blockage or knockout of H R increased the intrinsic excitability of LGP 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 LGP neurons through postsynaptic H R and H R, albeit its action was negatively regulated by the presynaptic H R, thereby suggesting possible role of histamine in motor deficits manifested in Parkinson's disease (PD).