Abstract
The hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are subthreshold, voltage-gated ion channels that are highly expressed in hippocampal and cortical pyramidal cell dendrites, where they are important for regulating synaptic potential integration and plasticity. We found that HCN1 subunits are also localized to the active zone of mature asymmetric synaptic terminals targeting mouse entorhinal cortical layer III pyramidal neurons. HCN channels inhibited glutamate synaptic release by suppressing the activity of low-threshold voltage-gated T-type (CaV3.2) Ca2+ channels. Consistent with this, electron microscopy revealed colocalization of presynaptic HCN1 and CaV3.2 subunit. This represents a previously unknown mechanism by which HCN channels regulate synaptic strength and thereby neural information processing and network excitability.
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Acknowledgements
We thank D.A. Brown (University College London), D. Johnston (University of Texas), M.C. Walker (University College London) and A. Constanti (University of London) for helpful discussions. We are also grateful to S. Martin (University College London) for genotyping the transgenic mice, K. Venner (University College London) for help with processing some samples for electron microscopy, D. McCarthy (University of London) for assistance with acquisition of some electron micrographs and H. Beck (University of Bonn) and K.P. Campbell (University of Iowa) for providing CaV3.2+/− breeding pairs. This work was supported by an MRC New Investigator Award (G0700369, M.M.S.), a Wellcome Trust project grant (WT087363MA, M.M.S.), a European Research Council Starter Independent Grant (ERC_2010_StG_20091118, M.M.S.), the Spanish Ministry of Science and Innovation (BFU-2009-08404/BFI and CONSOLIDER-Ingenio CSD2008-00005, R.L.), the Junta de Comunidades de Castilla-La Mancha (PAI08-0174-6967, R.L.), an Epilepsy Research UK Grant (0803, A.C.D.) and an MRC Project Grant (G0801756, A.C.D.). The monoclonal antibodies HCN1 (Clone N70/28) and CaV3.2 (Clone N55/10) were developed by and obtained from the University of California at Davis/US National Institutes of Health NeuroMab Facility, supported by US National Institutes of Health grant U24NS050606 and maintained by the University of California at Davis.
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Z.H. and M.M.S. performed and analyzed the electrophysiological experiments. Z.H., M.M.S. and R.L. performed the electron microscopy experiments. I.K. and A.C.D. performed western blot experiments and analysis. V.N.U. and J.J.R. provided valuable tools. M.M.S. designed the study and wrote the manuscript with contributions from all of the other authors.
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Huang, Z., Lujan, R., Kadurin, I. et al. Presynaptic HCN1 channels regulate CaV3.2 activity and neurotransmission at select cortical synapses. Nat Neurosci 14, 478–486 (2011). https://doi.org/10.1038/nn.2757
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DOI: https://doi.org/10.1038/nn.2757
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