Contribution of vestibular efferent system alpha-9 nicotinic receptors to vestibulo-oculomotor interaction and short-term vestibular compensation after unilateral labyrinthectomy in mice

Abstract

Sudden unilateral loss of vestibular afferent input causes nystagmus, ocular misalignment, postural instability and vertigo, all of which improve significantly over the first few days after injury through a process called vestibular compensation (VC). Efferent neuronal signals to the labyrinth are thought to be required for VC. To better understand efferent contributions to VC, we compared the time course of VC in wild-type (WT) mice and α9 knockout (α9−/−) mice, the latter lacking the α9 subunit of nicotinic acetylcholine receptors (nAChRs), which is thought to represent one signaling arm activated by the efferent vestibular system (EVS). Specifically, we investigated the time course of changes in the fast/direct and slow/indirect components of the angular vestibulo-ocular reflex (VOR) before and after unilateral labyrinthectomy (UL). Eye movements were recorded using infrared video oculography in darkness with the animal stationary and during sinusoidal (50 and 100°/s, 0.5–5 Hz) and velocity step (150°/s for 7–10 s, peak acceleration 3000°/s2) passive whole-body rotations about an Earth-vertical axis. Eye movements were measured before and 0.5, 2, 4, 6 and 9 days after UL. Before UL, we found frequency- and velocity-dependent differences between WT and α9−/− mice in generation of VOR quick phases. The VOR slow phase time constant (TC) during velocity steps, which quantifies contributions of the indirect component of the VOR, was longer in α9−/− mutants relative to WT mice. After UL, spontaneous nystagmus (SN) was suppressed significantly earlier in WT mice than in α9−/− mice, but mutants achieved greater recovery of TC symmetry and VOR quick phases. These data suggest (1) there are significant differences in vestibular and oculomotor functions between these two types of mice, and (2) efferent signals mediated by α9 nicotinic AChRs play a role during VC after UL.

Efferent Inputs Are Required for Normal Function of Vestibular Nerve Afferents

“…As such, under unstimulated normal conditions, efferent inputs could profoundly influence afferent activity. Consistent with the notion that efferents have a significant functional role, ␣9 KO mice (Eron et al, 2015;Hübner et al, 2015Hübner et al, , 2017 and calcitonin gene-related protein KO mice (Luebke et al, 2014) have deficiencies in the vestibulo-ocular reflex response, adaptation, and compensation.…”

Reviewing the Role of the Efferent Vestibular System in Motor and Vestibular Circuits

“…EVS signaling mediated by α9 nAChRs expressed at efferent vestibular synapses on hair cells, can elicit inhibitory responses in afferents (Elgoyhen et al, 1994 ; Hiel et al, 1996 ; Anderson et al, 1997 ; Holt et al, 2001 ; Zhou et al, 2013 ) (extensively reviewed in Jordan et al, 2013 ), while α6β2 nAChRs have been implicated in efferent-mediated afferent excitation of calyx/dimorphic neurons (Holt et al, 2015 ). It has been recently shown that α9 nAChRs may influence vestibular compensation following unilateral labyrinthectomy (Eron et al, 2015 ; Hübner et al, 2017 ). Given that the α9 subunit is expressed at EVN synapses, a missense mutation in the gene coding for this receptor subunit could compromise EVN output to the periphery.…”

Angular vestibuloocular reflex responses in Otop1 mice. II. Otolith sensor input improves compensation after unilateral labyrinthectomy

“…We did not measure the velocity storage time constant in Otop1 mice. The typical time constant for mice is smaller at 2-4 s (see, e.g., Eron et al 2015) compared with 15-25 s in primates (see, e.g., Raphan et al 1979). However, it is possible that a further reduction in velocity storage could hinder compensation especially at low frequencies, which is consistent with our data.…”