UCL School of Pharmacy, University College London, London, WC1N 1AX, UK.
Departamento de Ciencias Medicas, Universidad de Castilla-La Mancha, 02006 Albacete, Spain.
Sci Rep. 2017 Jan 10;7:40257. doi: 10.1038/srep40257.
The hyperpolarization-activated cyclic nucleotide-gated (HCN1) channels are predominantly located in pyramidal cell dendrites within the cortex. Recent evidence suggests these channels also exist pre-synaptically in a subset of synaptic terminals within the mature entorhinal cortex (EC). Inhibition of pre-synaptic HCN channels enhances miniature excitatory post-synaptic currents (mEPSCs) onto EC layer III pyramidal neurons, suggesting that these channels decrease the release of the neurotransmitter, glutamate. Thus, do pre-synaptic HCN channels alter the rate of synaptic vesicle exocytosis and thereby enhance neurotransmitter release? To address this, we imaged the release of FM1-43, a dye that is incorporated into synaptic vesicles, from EC synaptic terminals using two photon microscopy in slices obtained from forebrain specific HCN1 deficient mice, global HCN1 knockouts and their wildtype littermates. This coupled with electrophysiology and pharmacology showed that HCN1 channels restrict the rate of exocytosis from a subset of cortical synaptic terminals within the EC and in this way, constrain non-action potential-dependent and action potential-dependent spontaneous release as well as synchronous, evoked release. Since HCN1 channels also affect post-synaptic potential kinetics and integration, our results indicate that there are diverse ways by which HCN1 channels influence synaptic strength and plasticity.
超极化激活环核苷酸门控（HCN1）通道主要位于皮质中的锥体神经元树突内。最近的证据表明，这些通道也存在于成熟内嗅皮层（EC）中的一部分突触末梢的突触前。抑制突触前 HCN 通道可增强 EC 层 III 锥体神经元上的微小兴奋性突触后电流（mEPSC），表明这些通道减少了神经递质谷氨酸的释放。因此，突触前 HCN 通道是否会改变突触小泡胞吐的速率，从而增强神经递质的释放？为了解决这个问题，我们使用双光子显微镜在从前脑特异性 HCN1 缺陷小鼠、全局 HCN1 敲除及其野生型同窝仔鼠获得的切片中，对 EC 突触末梢中 FM1-43 的释放进行了成像，FM1-43 是一种可掺入突触小泡的染料。这与电生理学和药理学相结合表明，HCN1 通道限制了 EC 内一部分皮质突触末梢的胞吐速率，从而限制了非动作电位依赖性和动作电位依赖性自发性释放以及同步、诱发释放。由于 HCN1 通道还影响突触后电位动力学和整合，因此我们的结果表明，HCN1 通道影响突触强度和可塑性的方式多种多样。
