Received for publication May 16, 2006.
Revised July 28, 2006.
Accepted for publication July 28, 2006.

Enhancement of hippocampal pyramidal cell excitability by the novel selective sAHP channel blocker, UCL2077

Abstract

The slow afterhyperpolarization (sAHP) in hippocampal neurons has been implicated in learning and memory. However, its precise role in cell excitability and CNS function has not been explicitly tested for 2 reasons: (1) there are, at present, no selective inhibitors that effectively reduce the underlying current in vivo or in intact in vitro tissue preparations; and (2) though it is known that a small conductance K⁺ channel that activates following a rise in [Ca²⁺]_i underlies the sAHP, the exact molecular identity remains unknown. We show that UCL2077, a novel compound, suppressed the sAHP present in hippocampal neurons in culture (IC₅₀ = 0.5 µM) and in the slice preparation (IC₅₀ 10 µM). UCL2077 was selective, having minimal effects on Ca²⁺ channels, action potentials, input resistance and the medium AHP. UCL2077 also had little effect on heterologously expressed small conductance Ca²⁺-activated K⁺ (SK) channels. Moreover, UCL2077 and apamin, a selective SK channel blocker, affected spike firing in hippocampal neurons in different ways. These results provide further evidence that SK channels are unlikely to underlie the sAHP. This study also demonstrates that UCL2077, the most potent, selective sAHP blocker described so far, is a useful pharmacological tool for exploring the role of sAHP channels in the regulation of cell excitability in intact tissue preparations and, potentially, in vivo.

Key words: Ion channel regulation, Synaptic plasticity

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