Spindles are doin’ it for themselves: Glutamatergic autoexcitation in muscle spindles

Mention glutamate secretion to most physiologists, even neuroscientists, and they'll think only of excitatory synaptic neurotransmission in the central nervous system. Although by far its best known function, evidence from last 15 years shows it is also vital for controlling peripheral mechanosensory terminal responsiveness, via autogenic excitation. In an article appearing a previous issue The Journal Physiology, investigating rat muscle spindles (Bewick et al. 2005), we proposed that was released synaptic-like vesicles (SLVs), given ubiquitous presence SLVs terminals, their constitutive but stretch-modulated recycling, high levels vesicular transporter 1 (vGluT1), receptor exogenous ligands can alter stretch-evoked firing over wide range, abolish altogether. this study conducted Katherine Wilkinson's group provides first direct indeed (Than 2021). Than (2021) focus on manipulating vGluT1 activity monitor responses single afferents isolated mouse extensor digitorum longus (EDL) during sustained (ramp hold: static) rapidly changing (vibration: dynamic) stretches. Exogenous increased firing, whereas reducing loading into inhibition with xanthurenic acid (XA) or haploinsufficiency greatly reduced ability maintain stretch, often abolishing it. dynamic response rapid stretch vibration usually much less affected, although too occasionally blocked. It concluded endogenous release essential normal sensitivity sensory endings, particularly maintained vesicular. our experiments used whole-nerve electroneurograms pharmacology, unit recordings are spindle-specific impairing vesicle filling excitation glutamate. Interestingly, report substantial between-spindle variability experimental manipulations. some spindles, largely silenced, others were affected. few showed time-dependent inhibition, did not reach significance overall. This greater than studies. may reflect species differences (rat vs. mouse, deep lumbrical EDL), XA shorter (40 min) drug exposures. suggest inconsistent access might underlie variability. protocol, pharmacological agents applied at least h ensure maximal repeatability. Thus, both overall relative insensitivity slow these deeply embedded, highly encapsulated organs. A obvious, probably as important, source constitutive, SLV recycling. set baseline length duration experiment L0, which produces contractile tension. tonic will raise elevating hence initial excitability. blunt manipulations, saturate because haploinsufficient mice have loading. Combining findings role non-selective cation channel Piezo2, propose linear model (Fig. 1A), lengthening triggers Piezo2-dependent Na+ Ca2+ influx, possibly involving other channels. depolarization Ca2+-triggered directly initiates static firing. raises two immediate areas further study: if significant current flow occurs through there need explain potential's lack stretch-gated K+ component (Hunt al., 1978), well how glutamatergic activation ‘static-stretch’ channels be simultaneously prolonged (seconds constant stretch) stopped (cessation within milliseconds onset shortening). We recently alternative where same elements follow parallel interdependent pathways different timecourses & Banks, 2021) 1B C). Here, produce influx Piezo2 again enhances signalling slow, setting steady-state population stretch-activated channels, opposing continuous removal internalization. However, has issues: differentiated, why more sensitive manipulation? produced autoregulates spindle primary terminals. These models highlight new avenues understanding what does. intriguing see model, either, closely approximates actual mechanism eventually emerge. Watch space. authors declare they no competing interests. GB RB responsible conception design work; acquisition analysis interpretation data drafting work revising critically important intellectual content. Both approved final version manuscript submitted publication agree accountable all aspects No funding received.