Postnatal maturation of spinal dynorphin circuits and their role in somatosensation

Abstract

Inhibitory interneurons in the adult spinal dorsal horn (DH) can be neurochemically classified into subpopulations that regulate distinct somatosensory modalities. Although inhibitory networks in the rodent DH undergo dramatic remodeling over the first weeks of life, little is known about the maturation of identified classes of GABAergic interneurons, or whether their role in somatosensation shifts during development. We investigated age-dependent changes in the connectivity and function of prodynorphin (DYN)-lineage neurons in the mouse DH that suppress mechanosensation and itch during adulthood. In vitro patch clamp recordings revealed a developmental increase in primary afferent drive to DYN interneurons and a transition from exclusive C-fiber monosynaptic input to mixed A-fiber and C-fiber innervation. Although most adult DYN interneurons exhibited tonic firing as expected from their inhibitory phenotype, neonatal and adolescent DYN cells were predominantly classified as phasic or single-spiking. Importantly, we also found that most of the inhibitory presynaptic terminals contacting lamina I spinoparabrachial projection neurons (PNs) originate from DYN neurons. Furthermore, inhibitory synaptic input from DYN interneurons onto PNs was weaker during the neonatal period, likely reflecting a lower number of GABAergic terminals and a reduced probability of GABA release compared to adults. Finally, spinal DYN interneurons attenuated mechanical sensitivity throughout development, but this population dampened acute nonhistaminergic itch only during adulthood. Collectively, these findings suggest that the spinal “gates” controlling sensory transmission to the brain may emerge in a modality-selective manner during early life due to the postnatal tuning of inhibitory synaptic circuits within the DH.

Gucy2d selectively marks inhibitory dynorphin neurons in the spinal dorsal horn but is dispensable for pain and itch sensitivity

“…Spinal dynorphin neurons provide a substantial source of direct inhibition onto lamina I spinoparabrachial neurons 10 , 25 and therefore likely modulate nociceptive transmission to the brain. However, the spinal dynorphin population also includes excitatory neurons, thus requiring intersectional genetic strategies to selectively manipulate the inhibitory subset.…”

“…Spinal dynorphin neurons modulate itch and mechanical sensitivity, 10 , 18 , 29 , 32 and also provide inhibitory input onto a subset of lamina I spinoparabrachial neurons that respond to cold stimuli. 25 However, Gucy2d knockout mice exhibited no alterations in the response to CLQ-induced itch, chronic dry skin–mediated itch, or to mechanical, heat, or cold stimuli (Figs.…”

“…GABAergic neurons derived from the Pdyn lineage establish monosynaptic inputs onto lamina I spinoparabrachial neurons, 10 , 25 which transmit noxious signals to supraspinal centers. 5 , 30 , 57 However, in addition to the DH, dynorphin-expressing neurons are found in sensory ganglia, 55 the lateral hypothalamus, 14 bed nucleus of the stria terminalis, 17 and multiple regions of the neocortex.…”

Spinal GABAergic neurons are under feed-forward inhibitory control driven by Aδ and C fibers in Gad2 td-Tomato mice

“…22,[52][53][54][55] However, the primary inputs to GABAergic neurons in lamina II didn't display significant changes between young (P21) mice and adult (P49) mice. 56 GABAergic neurons of Gad67-EGFP mice has been comprehensively observed in other body regions which has been found highly expressed in the neocortical and hippocampal parts. 57 We have not addressed fluorescence expression patterns among other part of body in Gad2-td mice.…”

Spinal Inhibitory Interneurons: Gatekeepers of Sensorimotor Pathways

“…Galanin INs are entirely GABAergic and do not express glycinergic markers [ 111 ]; however, dynorphin INs also include excitatory neurons, particularly in the medial aspect of laminae I and II i [ 109 , 112 ]. Immature dynorphin INs receive predominantly C fiber input but by adulthood, they receive multimodal afferent input [ 113 , 114 ]. Axonal arborizations of dynorphin neurons are small and remain within the superficial dorsal horn [ 100 , 109 ], targeting excitatory neurons which are critical components of classical pain pathways, including somatostatin-expressing neurons [ 113 ] and gastrin-releasing peptide receptor (GRPR)-expressing INs [ 110 , 112 , 115 ], as well as lamina I spinoparabrachial neurons [ 56 , 114 ].…”