Turecek Josef, Jackman Skyler L, Regehr Wade G
1Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature. 2017 Nov 23;551(7681):503-506. doi: 10.1038/nature24474. Epub 2017 Oct 30.
At most synapses in the brain, short-term plasticity dynamically modulates synaptic strength. Rapid frequency-dependent changes in synaptic strength have key roles in sensory adaptation, gain control and many other neural computations. However, some auditory, vestibular and cerebellar synapses maintain constant strength over a wide range of firing frequencies, and as a result efficiently encode firing rates. Despite its apparent simplicity, frequency-invariant transmission is difficult to achieve because of inherent synaptic nonlinearities. Here we study frequency-invariant transmission at synapses from Purkinje cells to deep cerebellar nuclei and at vestibular synapses in mice. 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 calcium sensor for short-term facilitation, 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 Purkinje cell and vestibular synapses, Syt7 supports facilitation that is normally masked by depression, which can be revealed in wild-type mice but is absent in Syt7 knockout mice. In wild-type mice, facilitation increases with firing frequency and counteracts depression to produce frequency-invariant transmission. In Syt7-knockout mice, Purkinje cell 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 has an unexpected and important function in producing frequency-invariant transmission.
在大脑中的大多数突触处，短期可塑性会动态调节突触强度。突触强度的快速频率依赖性变化在感觉适应、增益控制和许多其他神经计算中起着关键作用。然而，一些听觉、前庭和小脑突触在很宽的放电频率范围内保持恒定强度，因此能够有效地编码放电率。尽管其看似简单，但由于固有的突触非线性，频率不变性传递很难实现。在这里，我们研究了从小脑浦肯野细胞到小脑深部核团的突触以及小鼠前庭突触处的频率不变性传递。这些突触的长时间激活会导致初始抑制，随后是稳态反应，在其生理活动范围内是频率不变的。我们发现，作为短期易化钙传感器的突触结合蛋白7（Syt7）存在于这两种突触中。目前尚不清楚为什么在这些以及其他抑制性突触中会存在易化传感器。我们发现，在浦肯野细胞和前庭突触处，Syt7支持通常被抑制所掩盖的易化，这种易化在野生型小鼠中可以显现，但在Syt7基因敲除小鼠中不存在。在野生型小鼠中，易化随放电频率增加，并抵消抑制作用以产生频率不变性传递。在Syt7基因敲除小鼠中，浦肯野细胞和前庭突触表现出传统的使用依赖性抑制，随着放电频率增加，减弱程度更大。突触前挽救Syt7表达可恢复易化和频率不变性传递。我们的结果确定了Syt7在表现出整体抑制的突触中的功能，并证明易化在产生频率不变性传递中具有意想不到的重要功能。
