Presynaptic inhibition of cutaneous afferents prevents self-generated itch

Abstract

Chronic itch represents an incapacitating burden on patients suffering a wide spectrum of diseases. Despite recent advances in our understanding of the cells and circuits implicated in the processing of itch information, chronic itch often presents itself without apparent cause. Here, we identify a spinal subpopulation of inhibitory neurons defined by the expression of Ptf1a involved in gating mechanosensory information self-generated during movement. These neurons receive tactile and motor input and establish presynaptic inhibitory contacts on mechanosensory afferents. Loss of Ptf1a neurons leads to increased hairy skin sensitivity and chronic itch, at least partially mediated through the classic itch pathway involving gastrin releasing peptide receptor (GRPR) spinal neurons. Conversely, chemogenetic activation of GRPR neurons elicits itch which is suppressed by concomitant activation of Ptf1a neurons. These findings shed new light on the circuit mechanisms implicated in chronic itch and open novel targets for therapy developments. Highlights* Ptf1a specifies adult spinal presynaptic neurons contacting cutaneous afferents * Loss of spinal Ptf1a+ neurons leads to self-generated itch and excessive grooming * Absence of Ptf1a+ neurons increases hairy skin sensitivity which triggers scratching * GRPR+ neurons act downstream of Ptf1a+ neurons in spontaneous itch