Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses

Abstract

At most synapses in the brain, short-term plasticity dynamically modulates synaptic strength. Rapid frequency-dependent changes in synaptic strength play critical roles in sensory adaptation, gain control and many other neural computations1,2. However, some auditory, vestibular and cerebellar synapses maintain constant strength over a wide range of firing frequencies3–5, and as a result efficiently encode firing rates. Despite its apparent simplicity, frequency-invariant transmission is difficult to achieve because of inherent synaptic nonlinearities6. Here we study frequency-invariant transmission at Purkinje cell to deep cerebellar nuclear (PC to DCN) synapses and vestibular synapses. Prolonged activation of these synapses leads to initial depression, which is followed by steady-state responses that are frequency invariant for their physiological activity range. We find that Synaptotagmin 7 (Syt7), a recently identified calcium sensor for short-term facilitation7, is present at both synapses. It was unclear why a sensor for facilitation would be present at these and other depressing synapses. We find that at PC and vestibular synapses, Syt7 supports a hidden component of facilitation that can be unmasked in wildtype animals but is absent in Syt7 knockout animals. In wildtype mice, facilitation increases with firing frequency and counteracts depression to produce frequency-invariant transmission. In Syt7 knockout mice, PC and vestibular synapses exhibit conventional use-dependent depression, weakening to a greater extent as the firing frequency is increased. Presynaptic rescue of Syt7 expression restores both facilitation and frequency-invariant transmission. Our results identify a function for Syt7 at synapses that exhibit overall depression, and demonstrate that facilitation plays an unexpected and important role in producing frequency-invariant transmission.