Failure of action potential propagation in sensory neurons: mechanisms and loss of afferent filtering in C‐type units after painful nerve injury

Abstract

Key points• The peripheral terminals of sensory neurons encode physical and chemical signals into trains of action potentials (APs) and transmit these trains to the CNS.• Although modulation of this process is thought to predominantly reside at synapses, there are also indications that AP trains are incompletely propagated past points at which axons branch. One such site is the T-junction, where the single sensory neuron axon branches into peripheral and central processes.• In recordings from sensory neurons of dorsal root ganglia excised from adult rats, we identified use-dependent failure of AP propagation between the peripheral and central processes that results in filtering of rapid AP trains, especially in C-type neurons.• Propagation failure was regulated by membrane input resistance and Ca 2+ -sensitive K + and Cl − currents. Following peripheral nerve injury, T-junction filtering is reduced in C-type neurons, which may possibly contribute to pain generation.Abstract The T-junction of sensory neurons in the dorsal root ganglion (DRG) is a potential impediment to action potential (AP) propagation towards the CNS. Using intracellular recordings from rat DRG neuronal somata during stimulation of the dorsal root, we determined that the maximal rate at which all of 20 APs in a train could successfully transit the T-junction (following frequency) was lowest in C-type units, followed by A-type units with inflected descending limbs of the AP, and highest in A-type units without inflections. In C-type units, following frequency was slower than the rate at which AP trains could be produced in either dorsal root axonal segments or in the soma alone, indicating that the T-junction is a site that acts as a low-pass filter for AP propagation. Following frequency was slower for a train of 20 APs than for two, indicating that a cumulative process leads to propagation failure. Propagation failure was accompanied by diminished somatic membrane input resistance, and was enhanced when Ca 2+ -sensitive K + currents were augmented or when Ca 2+ -sensitive Cl − currents were blocked. After peripheral nerve injury, following frequencies were increased in axotomized C-type neurons and decreased in axotomized non-inflected A-type neurons. These findings reveal that the T-junction in sensory neurons is a regulator of afferent impulse traffic. Diminished filtering of AP trains at the T-junction of C-type neurons with axotomized peripheral processes could enhance the transmission of activity that is ectopically triggered in a neuroma or the neuronal soma, possibly contributing to pain generation.

Effect of Electrical Field Stimulation on Dorsal Root Ganglion Neuronal Function

“…All testing was completed within three minutes following GFS. On the basis of prior studies and our own collision experiments using this preparation , recording of either a full AP or a reduced electrotonic residue in the soma was considered evidence of successful passage of an AP through the DRG, whereas complete failure of somatic depolarization was interpreted as failure of AP propagation through the DRG.…”

“…Third, we determined the ability of the recorded neuron to conduct APs through the DRG, which we quantified by identifying the maximal rate of APs in trains that successfully transited the DRG without AP failure. This last measure is relevant because the T‐junction where the stem axon of the pseudounipolar sensory neuron branches into the peripheral process and central process is a point of low safety factor for AP propagation due to impedance mismatch at that site, by which process the T‐junction functions as a low‐pass filter for afferent sensory traffic .…”

High-frequency modulation of rat spinal field potentials: effects of slowly conducting muscle vs. skin afferents

“…Electrical stimulation of nerve fibers with 100-Hz bursts is a common stimulation protocol to induce synaptic LTP (Ruscheweyh et al 2011). It has been shown that not all C fibers can follow this high frequency (Fang et al 2005;Gemes et al 2013;Lawson 2002;Raymond et al 1990). However, so far it remains unknown if slowly-conducting muscle and skin afferents differ systematically in their ability to follow electrical HFS.…”

Divergent effects of painful nerve injury on mitochondrial Ca2+ buffering in axotomized and adjacent sensory neurons

“…We have identified dysfunction of these processes in axotomized neurons following painful nerve injury, including elevated function of the plasma membrane Ca 2+ -ATPase (PMCA) (Gemes et al, 2012b), accompanied by decreased resting cytoplasmic Ca 2+ ([Ca 2+ ] c ) (Fuchs et al, 2005), reduced function of the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) (Duncan et al, 2013) that reduces ER Ca 2+ stores (Gemes et al, 2009; Rigaud et al, 2009), with resulting elevation of store-operated Ca 2+ entry (SOCE) (Gemes et al, 2011) and diminished release of Ca 2+ from stores upon neuronal activity through the process of Ca 2+ -induced Ca 2+ release. Together, these disturbances of Ca 2+ signaling contribute to elevated generation and transmission of high-frequency trains of action potentials in the injured sensory neurons (Gemes et al, 2009; Gemes et al, 2012a; Hogan et al, 2008; Lirk et al, 2008; Sapunar et al, 2005; Tang et al, 2012). …”