RT Journal Article SR Electronic T1 PIP2-Mediated HCN3 Channel Gating Is Crucial for Rhythmic Burst Firing in Thalamic Intergeniculate Leaflet Neurons JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 10412 OP 10423 DO 10.1523/JNEUROSCI.0021-11.2011 VO 31 IS 28 A1 Shui-Wang Ying A1 Gareth R. Tibbs A1 Alessandra Picollo A1 Syed Y. Abbas A1 R. Lea Sanford A1 Alessio Accardi A1 Franz Hofmann A1 Andreas Ludwig A1 Peter A. Goldstein YR 2011 UL http://www.jneurosci.org/content/31/28/10412.abstract AB Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate a pacemaking current, Ih, which regulates neuronal excitability and oscillatory activity in the brain. Although all four HCN isoforms are expressed in the brain, the functional contribution of HCN3 is unknown. Using immunohistochemistry, confocal microscopy, and whole-cell patch-clamp recording techniques, we investigated HCN3 function in thalamic intergeniculate leaflet (IGL) neurons, as HCN3 is reportedly preferentially expressed in these cells. We observed that Ih recorded from IGL, but not ventral geniculate nucleus, neurons in HCN2+/+ mice and rats activated slowly and were cAMP insensitive, which are hallmarks of HCN3 channels. We also observed strong immunolabeling for HCN3, with no labeling for HCN1 and HCN4, and only very weak labeling for HCN2. Deletion of HCN2 did not alter Ih characteristics in mouse IGL neurons. These data together indicate that the HCN3 channel isoform generated Ih in IGL neurons. Intracellular phosphatidylinositol-4,5-bisphosphate (PIP2) shifted Ih activation to more depolarized potentials and accelerated activation kinetics. Upregulation of HCN3 function by PIP2 augmented low-threshold burst firing and spontaneous oscillations; conversely, depletion of PIP2 or pharmacologic block of Ih resulted in a profound inhibition of excitability. The results indicate that functional expression of HCN3 channels in IGL neurons is crucial for intrinsic excitability and rhythmic burst firing, and PIP2 serves as a powerful modulator of Ih-dependent properties via an effect on HCN3 channel gating. Since the IGL is a major input to the suprachiasmatic nucleus, regulation of pacemaking function by PIP2 in the IGL may influence sleep and circadian rhythms.