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1 Institute of Basal Medicine, Department of Physiology, and Centre of Molecular Biology and Neuroscience, University of Oslo, PB 1103 Blindern, N-0317 Oslo, Norway
In hippocampal pyramidal cells, a single action potential (AP) or a burst of APs is followed by a medium afterhyperpolarization (mAHP, lasting
0.1 s). The currents underlying the mAHP are considered to regulate excitability and cause early spike frequency adaptation, thus dampening the response to sustained excitatory input relative to responses to abrupt excitation. The mAHP was originally suggested to be primarily caused by M-channels (at depolarized potentials) and h-channels (at more negative potentials), but not SK channels. In recent reports, however, the mAHP was suggested to be generated mainly by SK channels or only by h-channels. We have now re-examined the mechanisms underlying the mAHP and early spike frequency adaptation in CA1 pyramidal cells by using sharp electrode and whole-cell recording in rat hippocampal slices. The specific M-channel blocker XE991 (10 µM) suppressed the mAHP following 15 APs evoked by current injection at 60 mV. XE991 also enhanced the excitability of the cell, i.e. increased the number of APs evoked by a constant depolarizing current pulse, reduced their rate of adaptation, enhanced the afterdepolarization and promoted bursting. Conversely, the M-channel opener retigabine reduced excitability. The h-channel blocker ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride; 10 µM) fully suppressed the mAHP at 80 mV, but had little effect at 60 mV, whereas XE991 did not measurably affect the mAHP at 80 mV. Likewise, ZD7288 had little or no effect on excitability or adaptation during current pulses injected from 60 mV, but changed the initial discharge during depolarizing pulses injected from 80 mV. In contrast to previous reports, we found that blockade of Ca2+-activated K+ channels of the SK/KCa type by apamin (100400 nM) failed to affect the mAHP or adaptation. A computational model of a CA1 pyramidal cell predicted that M- and h-channels will generate mAHPs in a voltage-dependent manner, as indicated by the experiments. We conclude that M- and h-channels generate the somatic mAHP in hippocampal pyramidal cells, with little or no net contribution from SK channels.
(Received 18 March 2005;
accepted after revision 5 May 2005;
first published online 12 May 2005)
Corresponding author J. F. Storm: Department of Physiology at IMB and Centre for Molecular Biology and Neuroscience (CMBN), University of Oslo, PB 1103 Blindern, N-0317 Oslo, Norway. Email: jstorm{at}medisin.uio.no
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