Microglial Refinement of A-Fiber Projections in the Postnatal Spinal Cord Dorsal Horn Is Required for Normal Maturation of Dynamic Touch

Abstract

Sensory systems are shaped in postnatal life by the refinement of synaptic connectivity. In the dorsal horn of the spinal cord, somatosensory circuits undergo postnatal activity-dependent reorganisation, including the refinement of primary afferent A-fibre terminals from superficial to deeper spinal dorsal horn laminae which is accompanied by decreases in cutaneous sensitivity. Here we show in the mouse that microglia, the resident immune cells in the CNS, phagocytose A-fibre terminals in superficial laminae in the first weeks of life. Genetic perturbation of microglial engulfment during the initial postnatal period in either sex prevents the normal process of A-fibre refinement and elimination, resulting in altered sensitivity of dorsal horn cells to dynamic tactile cutaneous stimulation, and behavioural hypersensitivity to dynamic touch. Thus, functional microglia are necessary for the normal postnatal development of dorsal horn sensory circuits. In the absence of microglial engulfment, superfluous A-fibre projections remain in the dorsal horn and the balance of sensory connectivity is disrupted, leading to lifelong hypersensitivity to dynamic touch.Significance statement Dynamic touch is the sensation of movement across the skin, transmitted by mechanosensory A-fibres, the myelinated primary afferents that respond to innocuous mechanical stimulation. The central terminals of these fibres are located in the deep laminae of the sensory spinal cord dorsal horn in the adult. However, in early life they are widespread and retract from the superficial laminae of the dorsal horn during normal postnatal development. The underlying mechanisms remain unknown. We found that microglia phagocytose superfluous A-fibres and furthermore, disruption of this process leads to long-term aberrant dynamic touch processing and behaviour. Microglia mediated refinement of A-fibres during the early postnatal period is therefore critical to both normal dorsal horn development and appropriate spatial encoding of dynamic touch