Bicuculline-Sensitive Primary Afferent Depolarization Remains after Greatly Restricting Synaptic Transmission in the Mammalian Spinal Cord

Abstract

Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli. A major mechanism producing afferent presynaptic inhibition is via a channel-mediated depolarization of their intraspinal terminals which can be recorded extracellularly as a dorsal root potential (DRP). Based on measures of DRP latency it has been inferred that this primary afferent depolarization (PAD) of low-threshold afferents is mediated by minimally trisynaptic pathways with GABAergic interneurons forming last-order axoaxonic synapses onto afferent terminals. We used an in vitro rat spinal cord preparation under conditions that restrict synaptic transmission to test whether more direct low-threshold pathways can produce PAD. Mephenesin or high divalent cation solutions were used to limit oligosynaptic transmission. Recordings of synaptic currents in dorsal horn neurons and population synaptic potentials in ventral roots provided evidence that conventional transmission was chiefly restricted to monosynaptic actions. Under these conditions, DRP amplitude was largely unchanged but with faster time to peak and reduced duration. Similar results were obtained following stimulation of peripheral nerves. Even following near complete block of transmission with high Mg 2ϩ /low Ca 2ϩ -containing solution, the evoked DRP was reduced but not blocked. In comparison, in nominally Ca 2ϩ -free or EGTA-containing solution, the DRP was completely blocked confirming that Ca 2ϩ entry mediated synaptic transmission is required for DRP genesis. Overall these results demonstrate that PAD of low-threshold primary afferents can occur by more direct synaptic mechanisms, including the possibility of direct negative-feedback or nonspiking dendroaxonic pathways.

Requirement of neuronal connexin36 in pathways mediating presynaptic inhibition of primary afferents in functionally mature mouse spinal cord

“…2, bar graphs) the peak amplitude of the DRP evoked by 1.5 T stimulation was decreased by 21% and that of the DRP evoked by 2.5 T was decreased by 36% ( n = 4) by 20 μ m bicuculline. These results in juvenile mice are in agreement with the actions of GABA A antagonists on the DRP in neonatal rat and mouse whole cord preparations (Kremer & Lev‐Tov, 1998; Wong et al 2001) and those in the cat using picrotoxin (Eccles et al 1963; Rudomin et al 1990) and bicuculline (Curtis et al 1971), but the degree of depression is less than that reported in the hemisected spinal cord of neonatal (P7–14) rats (Shreckengost et al 2010).…”

“…Although the DRP is strongly associated with GABAergic mediation of presynaptic inhibition (reviewed by Rudomin & Schmidt, 1999; Rudomin, 2009), its attenuation by GABA antagonists ranges from partial (Rudomin et al 1990; Thompson & Wall, 1996; Kremer & Lev‐Tov, 1998; Wong et al 2001; present results –Fig. 2) to complete (Schreckengost et al 2010). GABA antagonists can, however, very effectively attenuate the long‐latency inhibition of the MSR evoked by conditioning stimulation (Fig.…”

Pre‐ and postsynaptic inhibitory control in the spinal cord dorsal horn

“…Activation of these receptors causes depolarization of PAFs in the rat spinal cord . Furthermore, the observation that PAD is not completely blocked by inhibition of synaptic transmission suggests that it could be partly mediated by either spillover of transmitters released from PAFs or a dendroaxonic reciprocal synaptic microcircuit . At the glomerular level, several dendrites contacting PAF central terminals contain clear vesicles, so these could be involved in the generation of PAD …”

Neural circuit flexibility in a small sensorimotor system

“…Cotransmission provides another level of complexity to sensorimotor integration, as to all aspects of neural signaling [26][45][77][78][79][80][81]. One well-studied multi-transmitter sensory neuron is GPR, which contains serotonin (5HT), acetylcholine (ACh) and allatostatin (AST) peptide [29][30][31][82].…”