Meissner corpuscles are mechanosensory end organs that densely occupy mammalian glabrous skin. We generated mice that selectively lacked Meissner corpuscles and found them to be deficient in both perceiving the gentlest detectable forces acting on glabrous skin and fine sensorimotor control. We found that Meissner corpuscles are innervated by two mechanoreceptor subtypes that exhibit distinct responses to tactile stimuli. The anatomical receptive fields of these two mechanoreceptor subtypes homotypically tile glabrous skin in a manner that is offset with respect to one another. Electron microscopic analysis of the two Meissner afferents within the corpuscle supports a model in which the extent of lamellar cell wrappings of mechanoreceptor endings determines their force sensitivity thresholds and kinetic properties.

Highlights d Two distinct mechanisms underlie PSI of cutaneous afferents and tactile sensitivity d GABA A Rs underlie homotypic activity-dependent PSI of afferents d Small-diameter afferents also engage heterotypic NMDARdependent PSI d Presynaptic GABA A Rs, not NMDARs, are necessary for texture discrimination In Brief Zimmerman et al. define distinct neurotransmitter and circuit mechanisms that gate the flow of tactile sensory information from the periphery into the spinal cord and characterize their roles in tactile sensitivity and behaviors. SUMMARYPresynaptic inhibition (PSI) of primary sensory neurons is implicated in controlling gain and acuity in sensory systems. Here, we define circuit mechanisms and functions of PSI of cutaneous somatosensory neuron inputs to the spinal cord. We observed that PSI can be evoked by different sensory neuron populations and mediated through at least two distinct dorsal horn circuit mechanisms. Lowthreshold cutaneous afferents evoke a GABA A -receptor-dependent form of PSI that inhibits similar afferent subtypes, whereas small-diameter afferents predominantly evoke an NMDA-receptor-dependent form of PSI that inhibits large-diameter fibers. Behaviorally, loss of either GABA A receptors (GABA A Rs) or NMDA receptors (NMDARs) in primary afferents leads to tactile hypersensitivity across skin types, and loss of GABA A Rs, but not NMDARs, leads to impaired texture discrimination. Post-weaning age loss of either GABA A Rs or NMDARs in somatosensory neurons causes systemic behavioral abnormalities, revealing critical roles of two distinct modes of PSI of somatosensory afferents in adolescence and throughout adulthood.Supplemental Information includes seven figures and two videos and can be found with this article online at https://doi.

Electron microscopy (EM) is a powerful tool for circuit mapping, but identifying specific cell types in EM datasets remains a major challenge. Here we describe a technique enabling simultaneous visualization of multiple, genetically identified neuronal populations so that synaptic interactions between them can be unequivocally defined. We present 15 AAV constructs and six mouse reporter lines for multiplexed EM labeling in the mammalian nervous system. These reporters feature dAPEX2, which exhibits dramatically improved signal compared to previously described ascorbate peroxidases. By targeting this enhanced peroxidase to different subcellular compartments, multiple orthogonal reporters can be simultaneously visualized and distinguished under EM using a protocol compatible with existing EM pipelines. Proof-of-principle double and triple EM labeling experiments demonstrated synaptic connections between primary afferents, descending cortical inputs, and inhibitory interneurons in the spinal cord dorsal horn. Our multiplexed peroxidase-based EM labeling system should therefore greatly facilitate analysis of connectivity in the nervous system.