BACKGROUND : The intrinsic cardiac nervous system (ICNS) refers to clusters of neurons, located within the heart, that participate in the neuronal regulation of cardiac functions and that are involved in the initiation of cardiac arrhythmias. Therefore, deciphering its role in cardiac physiology and physiopathology is mandatory. OBJECTIVE The aim of this study was to provide a phenotypic, elec[1]trophysiological, and pharmacological characterization of the mouse ICNS, which is still poorly characterized.

METHODS : Global cardiac innervation and phenotypic diversity were investigated using immunohistochemistry on cleared murine hearts and on tissue sections. The patch clamp technique was used for the electrophysiological and pharmacological characteriza[1]tion of isolated mouse intracardiac neurons.

RESULTS : We have identified the expression of 7 distinct neuronal markers within the mouse ICNS, thus proving the neurochemical di[1]versity of this network. Of note, it was the first time that the existence of neurons expressing the calcium-binding protein calbin[1]din, neuropeptide Y, and cocaine and amphetamine regulated tran[1]script peptide was described in the mouse. Electrophysiology studies also revealed the existence of 4 different neuronal popula[1]tions on the basis of their electrical behavior. Finally, we showed that these neurons can be modulated by several neuromodulators.

CONCLUSION : This study showed that the mouse ICNS presents a molecular and functional complexity similar to other species and is therefore a suitable model to decipher the role of individual neuronal subtypes regarding the modulation of cardiac function and the initiation of cardiac arrhythmias.

KEYWORDS : Intrinsic cardiac ganglia; Autonomic nervous system; Heart; Cardiac innervation; Peripheral neuron electrophysiology (Heart Rhythm 2022;-:1–11)

©2022 Heart Rhythm Society. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/)