TY - JOUR T1 - Selective T-Type Calcium Channel Block in Thalamic Neurons Reveals Channel Redundancy and Physiological Impact of <em>I</em><sub>Twindow</sub> JF - The Journal of Neuroscience JO - J. Neurosci. SP - 99 LP - 109 DO - 10.1523/JNEUROSCI.4305-09.2010 VL - 30 IS - 1 AU - Fanny M. Dreyfus AU - Anne Tscherter AU - Adam C. Errington AU - John J. Renger AU - Hee-Sup Shin AU - Victor N. Uebele AU - Vincenzo Crunelli AU - RĂ©gis C. Lambert AU - Nathalie Leresche Y1 - 2010/01/06 UR - http://www.jneurosci.org/content/30/1/99.abstract N2 - Although it is well established that low-voltage-activated T-type Ca2+ channels play a key role in many neurophysiological functions and pathological states, the lack of selective and potent antagonists has so far hampered a detailed analysis of the full impact these channels might have on single-cell and neuronal network excitability as well as on Ca2+ homeostasis. Recently, a novel series of piperidine-based molecules has been shown to selectively block recombinant T-type but not high-voltage-activated (HVA) Ca2+ channels and to affect a number of physiological and pathological T-type channel-dependent behaviors. Here we directly show that one of these compounds, 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), exerts a specific, potent (IC50 = 22 nm), and reversible inhibition of T-type Ca2+ currents of thalamocortical and reticular thalamic neurons, without any action on HVA Ca2+ currents, Na+ currents, action potentials, and glutamatergic and GABAergic synaptic currents. Thus, under current-clamp conditions, the low-threshold Ca2+ potential (LTCP)-dependent high-frequency burst firing of thalamic neurons is abolished by TTA-P2, whereas tonic firing remains unaltered. Using TTA-P2, we provide the first direct demonstration of the presence of a window component of Ca2+ channels in neurons and its contribution to the resting membrane potential of thalamic neurons and to the Up state of their intrinsically generated slow (&lt;1 Hz) oscillation. Moreover, we demonstrate that activation of only a small fraction of the T-type channel population is required to generate robust LTCPs, suggesting that LTCP-driven bursts of action potentials can be evoked at depolarized potentials where the vast majority of T-type channels are inactivated. ER -