Brandie Morris Verdone

The vestibular system of the inner ear provides head motion and orientation information required for maintaining balance and spatial orientation. Each of the five vestibular sensory organs contains type I and type II hair cells (HCs). Type I HCs are particularly notable for their evolutionary adaptability and unique calyceal synapses, in which the vestibular afferent nerve ending envelopes the HC body. In vitro studies indicate that calyceal synapses can transduce signals from HCs to afferents via nonquantal transmission, a mechanism proposed to be faster than conventional bouton synaptic transmission. In specialized regions of vestibular organs—striolae and central zones—many afferents form calyces that encase multiple type I HC bodies, suggesting that nonquantal transmission could be especially important in these regions. Consistently, striolar/central zone afferents are thought to preferentially mediate rapid and high-frequency stimulations. However, the direct consequences of selectively losing these HCs remain unknown. Here, we investigated the role of type I HCs within striolar/central zones by genetically ablating these cells. Reduction of type I HCs in these regions led to a loss of calyces and a compensatory increase in striolar type II HCs. These mutants exhibit reduced vestibular-evoked potentials, a response driven predominantly by striolar activity. In contrast, the vestibulo-ocular reflex, which is thought not to require striolar/central zone function, remained intact. Furthermore, loss of striolar/central zone-specific type I HCs causes head tremor in pups and abnormal head motion in adults, indicating that these HCs are essential for mediating head stability and postural control.

In afoveate species such as mice, it is accepted that gaze is typically redirected by head movements with a saccade-and-fixate strategy, while the eyes primarily stabilize vision within a limited oculomotor range. This view suggests that the accompanying eye movements are primarily reflexive, driven by mechanisms like the vestibulo-ocular reflex (VOR). However, emerging evidence challenges this assumption, suggesting that eye movements during active head motion may not be purely reflex-driven. Here, we directly test whether eye movements in mice are actively coordinated as part of voluntary gaze redirection rather than being reflexive. By systematically monitoring head and pupil positions during goal-directed orienting in a cohort of male mice, we find that mice generated active saccadic eye movements whose onsets are tightly linked to head movements. Furthermore, these saccadic eye movements occur at markedly shorter latencies than reflexive quick-phase eye movements evoked by comparable passive head rotations. Importantly, the interplay between coordinated eye and head movements during voluntary orienting resemble the predictable, stereotyped gaze patterns seen in foveate animals, such as primates. Our results suggest that mice possess an evolutionarily conserved mechanism for gaze redirection, integrating voluntary eye-head coordination similar to that of foveate vertebrates. These findings reframe the prevailing view by demonstrating an actively coordinated eye-head component to gaze redirection under goal-directed conditions in mice, complementing established reflexive mechanisms.

In afoveate species such as mice, it is accepted that gaze is typically redirected by head movements with a saccade-and-fixate strategy, while the eyes primarily stabilize vision within a limited oculomotor range. This view suggests that the accompanying eye movements are primarily reflexive, driven by mechanisms like the vestibulo-ocular reflex (VOR). However, emerging evidence challenges this assumption, suggesting that eye movements during active head motion may not be purely reflex-driven. Here, we directly test whether eye movements in mice are actively coordinated as part of voluntary gaze redirection rather than being reflexive. By systematically monitoring head and pupil positions during goal-directed orienting in a cohort of male mice, we find that mice generated active saccadic eye movements whose onsets are tightly linked to head movements. Furthermore, these saccadic eye movements occur at markedly shorter latencies than reflexive quick-phase eye movements evoked by comparable passive head rotations. Importantly, the interplay between coordinated eye and head movements during voluntary orienting resemble the predictable, stereotyped gaze patterns seen in foveate animals, such as primates. Our results suggest that mice possess an evolutionarily conserved mechanism for gaze redirection, integrating voluntary eye-head coordination similar to that of foveate vertebrates. These findings reframe the prevailing view by demonstrating an actively coordinated eye-head component to gaze redirection under goal-directed conditions in mice, complementing established reflexive mechanisms.

Vestibular hair cells (HCs) faithfully and rapidly detect head motions and gravity, driving motor reflexes that stabilize balance and gaze during locomotion. With the transition from water to land, the amniote vestibular inner ear added type I HCs, which differ from amniote type II HCs and anamniote HCs by their large calyx afferent synapse, non-quantal afferent transmission, and a large, low-voltage-activated K ⁺ conductance (g _K,L ). We recently showed that both g _K,L and the major type II K ⁺ conductances (A-type and delayed rectifier) require K _V 1.8 ( Kcna10 ) subunits. Here we compared K _V 1.8-null ( Kcna10 ^−/− ) and control animals to see how K _V 1.8 affects function as measured by receptor potentials and nonquantal postsynaptic potentials evoked by direct hair bundle motions, and by vestibulomotor behaviors. Recordings were taken from extrastriolar zones of the utricle. In both HC types, K _V 1.8 affected receptor potentials by reducing response time and gain, increasing dampening, and expanding the frequency bandwidth toward high frequencies. Effects are most prominent in type I HCs: lowpass corner frequencies of receptor potentials in Kcna10 ^−/− HCs of both types were ∼20 Hz, vs . ∼400 Hz in control type I and ∼70 Hz in control type II. We recorded nonquantal postsynaptic potentials from extrastriolar calyces, and found that the synaptic transfer function had lower gain and greater phase lag in Kcna10 ^−/− mice. In behavioral tests, Kcna10 ^−/− mice had vestibular-ocular reflexes with different response dynamics at low frequencies, impaired performance on a narrow balance beam, abnormal body posture and abnormal head motions in water and on land, and also rarely assumed bipedal stances. These vestibulomotor deficits in Kcna10 ^−/− mice likely reflect the changes noted in HCs, where K _V 1.8 expression is concentrated; that is, slower signaling of high-frequency head motions by Kcna10 ^−/− HCs fails to fully stabilize body and head position during locomotion. Thus, g _K,L (K _V 1.8) contributes to fast signal transmission in the amniote vestibular inner ear and supports improved performance on challenging vestibulomotor tasks. Graphical

Summary: Expanded intronic G ₄ C ₂ repeats in the C9orf72 gene cause several cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeats are translated through a non-AUG-dependent mechanism into five different dipeptides (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and eventually neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating in primary neurons in-vitro and CNS tissue in-vivo . Importantly, this interaction improves the overall survival of neurons expressing GR. Downregulation of Kap β2 is detrimental to the survival of neurons only if GR is expressed, whereas increased Kap β2 levels mitigate GR-mediated neurotoxicity. notably, we did not find any changes in TDP-43 localization nor in the dynamic properties of the GR aggregates when Kapβ2 was over-expressed. These findings support the design of therapeutic strategies aimed at modulating Kap β2 levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.

A G4C2 hexanucleotide repeat expansion in theC9orf72gene is the most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed in regions of neurodegeneration. The accumulation of repetitive RNAs and dipeptide repeat protein (DPR) are two proposed mechanisms of toxicity in C9-ALS/FTLD and linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport is regulated by the phenylalanine-glycine nucleoporins (FG nups) that comprise the nuclear pore complex (NPC) permeability barrier. However, the relationship between FG nups and TDP-43 pathology remains elusive. Our studies show that nuclear depletion and cytoplasmic mislocalization of one FG nup, NUP62, is linked to TDP-43 mislocalization in C9-ALS/FTLD iPSC neurons. Poly-glycine arginine (GR) DPR accumulation initiates the formation of cytoplasmic RNA granules that recruit NUP62 and TDP-43. Cytoplasmic NUP62 and TDP-43 interactions promotes their insolubility and NUP62:TDP-43 inclusions are frequently found in C9orf72 ALS/FTLD as well as sporadic ALS/FTLD postmortem CNS tissue. Our findings indicate NUP62 cytoplasmic mislocalization contributes to TDP-43 proteinopathy in ALS/FTLD.