Microglial refinement of A-fibre projections in the postnatal spinal cord dorsal horn is required for normal maturation of dynamic touch

Abstract

In the spinal cord dorsal horn, sensory circuits undergo remarkable postnatal reorganisation, including refinement of primary afferent A-fibres in the superficial layers, accompanied by decreased cutaneous sensitivity. Here we show a physiological role of microglia necessary for normal development of dorsal horn sensory circuits and tactile sensitivity. In the absence of microglial engulfment, superfluous A-fibre projections persist, leading to lifelong hypersensitivity to dynamic touch.

Microglial phagocytosis mediates long-term restructuring of spinal GABAergic circuits following early life injury

“…An over-pruning of A-fibres following incision will likely alter the pattern of tactile input to the dorsal horn and affect behavioural sensitivity long-term. This is supported by our recent finding that microglial dysfunction in neonates lead to structural, functional and behavioural changes in adults (Xu et al, 2021). Alternatively, the engulfment of A-fibres could be a homeostatic response to A-fibre sprouting, which has been observed in neonatal animals following nerve transection and hindpaw inflammation (Fitzgerald, 1985;Fitzgerald et al, 1990;Ruda et al, 2000) and is supported by electrophysiology studies showing that neonatal incision increased peripheral afferent drive and monosynaptic A-fibre inputs onto lamina I projection neurons in adulthood (Li et al, 2015).…”

“…In contrast to neonates, A-fibre engulfment was not altered following hindpaw incision in adults. Previous reports have shown that hyperalgesia could only be induced if injury happened within a critical period (1st postnatal week) (Walker et al, 2009), which coincides with the maturation period for A-fibres (Xu et al, 2021). Therefore, it is possible that A-fibres are protected from engulfment once the critical period is closed.…”

“…A-fibre terminal distribution and inhibitory circuits mature and undergo plastic changes over the first postnatal week (Koch et al, 2012;Koch & Fitzgerald, 2013), with microglia actively engulfing A-fibres as part of normal development (Xu et al, 2021). This might render them more susceptible to external perturbations and could explain why A-fibre and VGAT presynaptic terminals are engulfed following peripheral injury, but VGLUT2 presynaptic terminals are not.…”

“…Microglia regulate developmental pruning of synapses in the brain and spinal cord (Paolicelli et al, 2011;Schafer et al, 2012a;Vainchtein et al, 2018;Vukojicic et al, 2019), and we have recently shown that microglia are critical for the postnatal refinement of sensory A-fibre projections in the dorsal horn (Xu et al, 2021). In addition, it has been shown that microglia cells can exhibit innate immune memory, by which a stimulus causes microglia to enter a 'trained' state which alters their future response to inflammatory challenges (Neher & Cunningham, 2019).…”

The Bayliss–Starling Prize Lecture: The developmental physiology of spinal cord and cortical nociceptive circuits

“…Perhaps as a result of this, there is a striking, transient projection of A fibres to the superficial laminae of the immature dorsal horn, which are the central target for C fibre nociceptor terminals in the adult. This phenomenon, originally observed using fibre-tracing methods (Beggs et al, 2002;Granmo et al, 2008), has recently been confirmed by mapping the exuberant A fibre terminals in the immature spinal dorsal horn in vesicular glutamate transporter 1(VGluT1) reporter mice and demonstrating their gradual withdrawal from superficial laminae by microglial engulfment (Xu et al, 2023) Electrophysiological analysis shows that although C fibre terminals do make some synaptic connections in the superficial dorsal horn from birth, these are weak and sparse, and C fibre evoked activity is not transmitted to the deeper, WDR, presumptive projection neurons until the second postnatal week (Baccei et al, 2003;Fitzgerald, 1988;Fitzgerald & Jennings, 1999). Thus, dorsal horn neurons in the deeper laminae respond only to short-latency A fibre-mediated responses until P7−P8.…”