Implementation of Linear Sensory Signaling via Multiple Coordinated Mechanisms at Central Vestibular Nerve Synapses

Abstract

Summary Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate-coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations.

Synaptic Specializations Support Frequency-Independent Purkinje Cell Output from the Cerebellar Cortex

“…This suggests that depression arising from frequency-dependent spike invasion does not contribute significantly to depression under our experimental conditions. The linear frequency dependence of charge transfer is an unusual synaptic property that has also been observed at glutamatergic afferents in vestibular nuclei (Bagnall et al, 2008; McElvain et al, 2015). We find that at the PC-DCN synapse linear charge transfer appears to arise from a number of synaptic specializations, including an unexpected component of short-term facilitation that is normally masked by depression.…”

“…For most depressing synapses, increased firing frequency leads to more pronounced depression (Abbott et al, 1997; Brenowitz et al, 1998; Galarreta and Hestrin, 1998; Cook et al, 2003), with the exception of vestibular afferents in vestibular nuclei (Bagnall et al, 2008; McElvain et al, 2015) and possibly auditory inputs in the chick brainstem (Macleod et al 2007). At the PC-DCN synapse in very young animals, depression is frequency-dependent and it has been proposed that this is due to the failure or attenuation of action potentials upon invasion of presynaptic boutons at high frequency (Kawaguchi and Sakaba, 2015).…”

“…According to this model, each release site contains two releasable vesicles but release is limited to a single vesicle per release site per stimulus. Consequently, vesicles are always available for release, and depression is determined by frequency-independent decreases in release probability (McElvain et al, 2015). Since PC-DCN synapses facilitate, and the magnitude of facilitation is frequency dependent, it does not conform to the model of the vestibular synapse.…”

“…Frequency independent release has been observed at only a few other synapses, including vestibular synapses (Bagnall et al, 2008; McElvain et al, 2015) and possibly in the chick auditory brainstem (MacLeod et al, 2007). At most depressing synapses the extent of depression becomes more pronounced as the stimulus frequency is increased, and as a result the frequency-dependence of charge transfer is sublinear.…”

Physical determinants of vesicle mobility and supply at a central synapse

“…Some of these conventional synapses, such as those formed by cerebellar mossy fibre terminals (MFTs) or vestibular nerve fibres, have a readily releasable pool (RRP) of only 1–2 vesicles per AZ, which are docked and primed and ready for release. A much larger releasable pool (RP) containing 200–300 vesicles resides nearby and these vesicles can be supplied to the AZ, docked and primed at a combined rate of 40–80 s −1 (with all three steps referred together as reloading) to refill the RRP ( Saviane and Silver, 2006 ; Hallermann et al, 2010 ; McElvain et al, 2015 ). Even when the large RP is depleted by sustained high-frequency stimulation, release rates of 7–8 s −1 can be sustained by replenishment from a large vesicle reserve pool (R) at these synapses ( Saviane and Silver, 2006 ; McElvain et al, 2015 ).…”