Post-activation depression from primary afferent depolarization (PAD) produces extensor H-reflex suppression following flexor afferent conditioning.

Suppression of the extensor H-reflex by flexor afferent conditioning is thought to be produced by a long-lasting inhibition of extensor Ia-afferent terminals via GABAA receptor-activated primary afferent depolarization (PAD). Considering the recent finding that PAD does not produce presynaptic inhibition of Ia-afferent terminals, we examined in 28 participants if H-reflex suppression is instead mediated by post-activation depression of the extensor Ia-afferents triggered by PAD-evoked spikes and/or by a long-lasting inhibition of the extensor motoneurons. A brief conditioning vibration of the flexor tendon suppressed both the extensor soleus H-reflex and the tonic discharge of soleus motor units out to 150 ms following the vibration, suggesting that part of the H-reflex suppression during this time was mediated by postsynaptic inhibition of the extensor motoneurons. When activating the flexor afferents electrically to produce conditioning, the soleus H-reflex was also suppressed but only when a short-latency reflex was evoked in the soleus muscle by the conditioning input itself. In mice, a similar short-latency reflex was evoked when optogenetic or afferent activation of GABAergic (GAD2+) neurons produced a large enough PAD to evoke orthodromic spikes in the test Ia-afferents, causing post-activation depression of subsequent monosynaptic excitatory postsynaptic potentials. The long duration of this post-activation depression and related H-reflex suppression (seconds) was similar to rate-dependent depression that is also due to post-activation depression. We conclude that extensor H-reflex inhibition by brief flexor afferent conditioning is produced by both post-activation depression of extensor Ia-afferents and long-lasting inhibition of extensor motoneurons, rather than from PAD inhibiting Ia-afferent terminals. KEY POINTS: Suppression of extensor H-reflexes by flexor afferent conditioning was thought to be mediated by GABA A receptor-mediated primary afferent depolarization (PAD) shunting action potentials in the Ia afferent terminal. In line with recent findings that PAD has a facilitatory role in Ia afferent conduction, we show here that when large enough, PAD can evoke orthodromic spikes that travel to the Ia afferent terminal to evoke excitatory postsynaptic potentials in the motoneuron. These PAD-evoked spikes also produce post-activation depression of Ia afferent terminals and may mediate the short and long-lasting suppression of extensor H-reflexes in response to flexor afferent conditioning. Our findings highlight that we must reexamine how changes in the activation of GABAergic interneurons and PAD following nervous system injury or disease affects the regulation of Ia afferent transmission to spinal neurons and ultimately motor dysfunction in these disorders. Abstract figure legend We propose that stimulation of flexor afferents activate GABAergic interneurons (GABA axo neuron) with axoaxonic connections to or near dorsal nodes of Ranvier (yellow) in extensor Ia afferents. If large enough this nodal PAD, mediated by GABA A receptors (blue), will activate spikes in the extensor Ia afferent (top green arrow) that travel to the extensor motoneuron to produce an excitatory postsynaptic potential and post-activation depression of subsequent H-reflexes evoked by direct extensor Ia afferents. We also hypothesize that PAD-evoked spikes in other branches of the extensor Ia afferent (bottom green arrow) activate more ventrally located GABA axo interneurons with projections to the Ia afferent terminal where GABA B receptors (red) are activated to also produce post-activation depression of subsequent extensor H-reflexes. This article is protected by copyright. All rights reserved.