Astrocytes mediate priming of spinal nociceptive circuits

PROJECT SUMMARY/ABSTRACT 9% of children born in the United States are admitted to the neonatal intensive care unit where many experience invasive surgical procedures as part of their medical care. The resulting tissue damage leads to ‘priming’ of the nociceptive pathway, causing increased pain perception in response to noxious stimuli later in life. Long-term potentiation (LTP) of sensory synapses onto projection neurons (PN) in the spinal superficial dorsal horn (SDH) likely contributes to the sensitization of spinal pain circuits by amplifying ascending nociceptive transmission to the brain. While primary afferent-to-PN synapses typically follow ‘Hebbian’ spike timing dependent plasticity (STDP), in which presynaptic firing just prior to postsynaptic firing induces LTP, neonatal incision widens the window of stimulation that induces potentiation, facilitating the amplification of pain transmission. It is becoming increasingly clear that astrocytes are critical modulators of synaptic transmission, capable of altering the subunit composition of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors. However, nothing is known about how astrocyte-synapse communication is involved in the priming of nociceptive circuits, posing a critical gap in knowledge as insight into astrocytic regulation of plasticity in spinal PNs will advance our understanding of the molecular basis of STDP, and potentially reveal novel therapeutic targets to attenuate long-term amplification of nociceptive transmission. The long-term goal is to facilitate development of chronic pain treatments by advancing our understanding of central nociceptive circuit development. The short-term goal of this application is to elucidate the role of astrocytes in STDP of sensory synapses onto SDH PNs involved in the priming of pain pathways after early life injury. Prior studies demonstrate that neonatal incision persistently increases CP AMPAR expression and relaxes the rules of STDP in PNs. Recent evidence that astrocytes dynamically inflect plasticity and selectively modulate AMPAR subunit clustering via secreted factors support the concept that astrocytes are critical for the synaptic changes occurring as a result of neonatal priming. The central hypothesis is that astrocytes reacting to neonatal surgical incision secrete factors that recruit Ca2+ permeable (CP) AMPAR, thus fostering an environment permissive to non-Hebbian LTP at primary afferent-to-PN synapses. This hypothesis will be tested via two aims. Aim 1 will identify the role of astrocytes in reorganizing postsynaptic glutamate receptor expression after neonatal injury, while Aim 2 will determine the degree to which astrocytes facilitate LTP in the SDH after early life injury. The proposed research will identify novel mechanisms by which spinal astrocytes modify glutamate receptor expression and contribute to the development of persistent changes in activity-dependent potentiation of sensory synapses onto PNs. Results will further our understanding of how neuron-glial interactions are involved in the persistent changes to synaptic plasticity of spinal nociceptive circuits involved in neonatal priming, which will contribute to foundational knowledge for developing therapeutics that disrupt aberrant potentiation.