du Lac, S. | bioRxiv Science

bioRxiv2025

Functional contributions of quantal and non-quantal hair cell synaptic transmission in the vestibular periphery

Information about head motion and gravity is conveyed to the brain by vestibular nerve afferents which are subdivided by their spontaneous firing properties into regular and irregular subtypes thought to be differentially responsible for vestibulo-ocular vs vestibulo-spinal reflexes. In the vestibular periphery, afferents make glutamatergic synapses with type II hair cells (HCs) in all vertebrates. During the evolutionary transition to land, however, amniotes (reptiles, birds, and mammals) additionally developed type I vestibular HCs in which unique calyceal afferent terminals cover the basolateral walls of one or more HCs, enabling a nonquantal (NQ) form of synaptic transmission. Most afferents receive inputs from both types of HCs, but the roles of type I vs type II HCs in generating vestibular afferent firing patterns and behaviors remains unclear. Using optogenetics in mice (both sexes), we confirm that stimulation of type II HCs drives conventional quantal glutamatergic transmission, whereas type I HC stimulation evokes nonquantal responses. In mice with disrupted glutamatergic quantal transmission, NQ transmission effectively drove afferent responses to a wide range of head movement frequencies, as assessed by both vestibular sensory evoked potentials and the vestibulo-ocular reflex. Although the distribution of afferent discharge regularity was unaffected, loss of glutamatergic transmission impaired detection of gravity as evidenced by abnormal contact righting reflex behavior. These results indicate that nonquantal glutamatergic transmission from type I HCs is sufficient to generate normal afferent firing patterns and dynamic vestibular behaviors and that glutamatergic release from type II HCs is required for the detection of gravity. Significance StatementThe vestibular system enables balance and spatial orientation by detecting head movements and gravity. During vertebrate evolution, amniotes developed a unique form of synaptic communication--non-quantal (NQ) transmission--between type I hair cells and calyceal afferent nerve fibers in vestibular sensors. This study reveals that NQ transmission can robustly drive vestibular responses across a wide stimulus range, even in the absence of conventional glutamate-based (quantal) signaling. Using electrophysiology, optogenetics and behavioral assays, we show that NQ and quantal transmission serve distinct but complementary roles: NQ supports rapid, broad-range signaling, while quantal transmission is critical for precise gravity detection. These findings highlight how evolutionary innovations in synaptic transmission enhance vestibular function, contributing to our understanding of balance disorders and sensory processing.

neuroscience↗

bioRxiv2024

Tau P301S Transgenic Mice Develop Gait and Eye Movement Impairments That Mimic Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with an estimated prevalence of 5-7 people in 100,000. Clinically characterized by impairments in gait, balance, and eye movements, as well as aggregated Tau pathology, PSP leads to death in approximately 5-8 years. No disease-modifying treatments are currently available. The contribution of Tau pathology to the symptoms of patients with PSP is poorly understood, in part due to lack of a rodent model that recapitulates characteristic aspects of PSP. Here, we assessed the hTau.P301S mouse for key clinical features of PSP, finding progressive impairments in balance and gait coordination. Additionally, we found impairments in fast vertical eye movements, one of the most distinctive features of PSP. Across animals, we found that Tau pathology in motor control regions correlated with motor deficits. These findings highlight the utility of the hP301S mouse in modeling key aspects of PSP.

neuroscience↗

bioRxiv2020

Modular output circuits of the fastigial nucleus mediate diverse motor and nonmotor functions of the cerebellar vermis

The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fastigial cell type is connected with a specific set of Purkinje cells and inferior olive neurons and in turn innervates a distinct collection of downstream targets. Transsynaptic tracing indicates extensive disynaptic links with cognitive, affective, and motor forebrain circuits. These results indicate that diverse cerebellar vermis functions are mediated by modular synaptic connections of distinct fastigial cell types which differentially coordinate posturomotor, oromotor, positional-autonomic, orienting, and vigilance circuits.

neuroscience↗