An apamin-sensitive Ca ²⁺ -activated K ⁺ current in hippocampal pyramidal neurons

Abstract

In hippocampal and other cortical neurons, action potentials are followed by afterhyperpolarizations (AHPs) generated by the activation of small-conductance Ca 2؉ -activated K ؉ channels (SK channels). By shaping the neuronal firing pattern, these AHPs contribute to the regulation of excitability and to the encoding function of neurons. Here we report that CA1 pyramidal neurons express an AHP current that is suppressed by apamin and is involved in the control of repetitive firing. This current presents distinct kinetic and pharmacological features, and it is modulated differently than the apamin-insensitive slow AHP current. Furthermore, our in situ hybridizations show that the apaminsensitive SK subunits are expressed in CA1 pyramidal neurons, providing a potential molecular correlate to the apaminsensitive AHP current. Altogether, these results clarify the discrepancy between the reported high density of apaminbinding sites in the CA1 region and the apparent lack of an apamin-sensitive current in CA1 pyramidal neurons, and they may explain the effects of this toxin on hippocampal synaptic plasticity and learning.In many neurons of the central nervous system, action potentials are followed by a rise in intracellular Ca 2ϩ leading to a prolonged afterhyperpolarization (AHP) of the membrane (1-4). The currents underlying the AHP are mediated by small-conductance voltage-insensitive Ca 2ϩ -activated K ϩ channels (SK channels), and they can be classified into two groups on the basis of their kinetic and pharmacological properties (5): (i) I AHP is sensitive to the bee venom toxin apamin and presents a relatively fast activation and decay (6); (ii) sI AHP (where s stands for slow) is apamin insensitive, rises to peak and decays with time constants of several hundreds of milliseconds, and is modulated by many neurotransmitters (1, 4). Functionally, activation of I AHP controls the firing frequency in tonically spiking neurons, whereas activation of sI AHP leads to spike frequency adaptation (5). While most excitable cells present an apamin-sensitive I AHP , only a few nerve cells exhibit an apamin-insensitive sI AHP , or both types of currents (4, 5). In the hippocampus, electrophysiological experiments have so far shown a peculiar segregation of AHP currents in different types of neurons, with pyramidal neurons presenting exclusively sI AHP (1, 7), and oriens-alveus interneurons only I AHP (8). These results are in contrast with studies on the distribution of apamin-binding sites in rat brain sections, which show the highest density in the hippocampal CA1 region (9, 10).Three members of the SK family of K ϩ channels have recently been cloned (11). All of them are voltage-insensitive and activated by submicromolar intracellular Ca 2ϩ . Two of them, SK2 and SK3, are blocked by apamin, whereas SK1 is apamin insensitive (11). Given these features, the SK channel subunits cloned so far are likely to participate in the formation of native SK channels, giving rise to apamin-sensitive and -insensitive AHP currents i...

Functional Specificity of Gαqand Gα11in the Cholinergic and Glutamatergic Modulation of Potassium Currents and Excitability in Hippocampal Neurons

“…The pharmacological separation by apamin (Fig. 1 A) suggests that I AHP and sI AHP are distinct currents, as reported previously in rat CA1 pyramidal neurons (Stocker et al, 1999). In all CA1 pyramidal neurons from mouse, as in rat, the Ca 2ϩ spikes and sI AHP remained stable for the duration of the recording (usually ϳ2-3 hr).…”

“…No discrepancies in the variations of these parameters on pharmacological manipulations were observed; therefore, in Results and the figures, we reported only the values concerning I AHP and sI AHP amplitudes. The amplitude of I AHP was determined at the peak of the current, whereas that of sI AHP was determined at a point 700 -800 msec after the end of the command pulse, in which a possible contamination by the partially overlapping I AHP was negligible (Stocker et al, 1999). Values are presented as mean Ϯ SEM.…”

“…Rat CA1 pyramidal neurons have been shown to present two distinct Ca 2ϩ -dependent afterhyperpolarizing currents, contributing to the early and late spike frequency adaptation: I AHP , deactivating in hundreds of milliseconds and sensitive to the toxin apamin; and sI AHP , characterized by a slow deactivation (in the range of seconds), insensitive to apamin and sensitive to the neuromodulatory effects of a number of transmitters (Stocker et al, 1999). In mouse hippocampal pyramidal neurons, the types of AHP currents and their key features are still unexplored.…”

Ionic and neuromodulatory regulation of burst discharge controls frequency tuning

“…Muscarinic receptor activation has been found to alter the firing properties of individual neurons through the modulation of a number of individual ionic conductances (Chen and Johnston, 2004;Delgado-Lezama et al, 1997;Stocker et al, 1999). In order to determine if the effects of mAChR activation resulted from the regulation of one or several ion channels, we used an in vitro ELL slice preparation (Turner et al, 1994(Turner et al, , 1996.…”

Synaptic plasticity in early aging

“…Time 0 shows the events that transpire after the arrival of a theta burst (four action potentials in 30 ms) over the glutamatergic input. Initially this causes a pronounced depolarization of the target cell (indicated by red) but this is quickly counterbalanced by activation voltage-and calcium-dependent potassium channels that generate AHPs lasting from tens of milliseconds to seconds (Stocker et al, 1999;Kramár et al, 2004). These AHPs, initiated by the early bursts, tend to reduce the depolarization associated with subsequent bursts.…”