Papers of the Week

Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent synapses onto spinal projection neurons. However, the cellular localization of the D1/D5Rs driving non-Hebbian LTP in spinal nociceptive circuits remains unknown, and it is also unclear whether D1/D5R signaling must occur concurrently with sensory input in order to promote non-Hebbian LTP at these synapses. Here we investigate these issues using cell type-selective knockdown of D1Rs or D5Rs from lamina I spinoparabrachial neurons, dorsal root ganglion (DRG) neurons or astrocytes in adult mice of either sex using Cre recombinase-based genetic strategies. The LTP evoked by low-frequency stimulation of primary afferents in the presence of the selective D1/D5R agonist SKF82958 persisted following the knockdown of D1R or D5R in spinoparabrachial neurons, suggesting that postsynaptic D1/D5R signaling was dispensable for non-Hebbian plasticity at sensory synapses onto these key output neurons of the superficial dorsal horn (SDH). Similarly, the knockdown of D1Rs or D5Rs in DRG neurons failed to influence SKF82958-enabled LTP in lamina I projection neurons. In contrast, SKF82958-induced LTP was suppressed by the knockdown of D1R or D5R in spinal astrocytes. Furthermore, the data indicate that the activation of D1R/D5Rs in spinal astrocytes can either retroactively or proactively drive non-Hebbian LTP in spinoparabrachial neurons. Collectively, these results suggest that dopaminergic signaling in astrocytes can strongly promote activity-dependent LTP in the SDH, which is predicted to significantly enhance the amplification of ascending nociceptive transmission from the spinal cord to the brain. Long-term potentiation (LTP) of sensory synapses onto lamina I projection neurons represents a key mechanism by which the spinal superficial dorsal horn (SDH) can amplify ascending nociceptive transmission to the brain. Here we demonstrate that the activation of D1 or D5 dopamine receptors expressed in spinal astrocytes promotes non-Hebbian LTP at primary afferent inputs onto mouse spinoparabrachial neurons. Furthermore, astrocyte D1/D5R signaling not only retroactively potentiated sensory synapses that were recently active, but also proactively primed synapses to undergo LTP following subsequent stimulation. These results identify dopaminergic signaling onto astrocytes as a key regulator of synaptic metaplasticity in the SDH and suggest that astrocyte D1/D5Rs could serve as a gain control that enables the excessive amplification of spinal nociceptive transmission.