KCNQ channel subunits are widely expressed in peripheral and central neurons, where they give rise to a muscarinic-sensitive, subthreshold, and noninactivating K ϩ current (M-current). It is generally agreed that activation of KCNQ/M channels contributes to spike frequency adaptation during sustained depolarizations but is too slow to influence the repolarization of solitary spikes. This concept, however, is based mainly on experiments with muscarinic agonists, the multiple effects on membrane conductances of which may overshadow the distinctive effects of KCNQ/M channel block. Here, we have used selective modulators of KCNQ/M channels to investigate their role in spike electrogenesis in CA1 pyramidal cells. Solitary spikes were evoked by brief depolarizing current pulses injected into the neurons. The KCNQ/M channel blockers linopirdine and XE991 markedly enhanced the spike afterdepolarization (ADP) and, in most neurons, converted solitary ("simple") spikes to high-frequency bursts of three to seven spikes ("complex" spikes). Conversely, the KCNQ/M channel opener retigabine reduced the spike ADP and induced regular firing in bursting neurons. Selective block of BK or SK channels had no effect on the spike ADP or firing mode in these neurons. We conclude that KCNQ/M channels activate during the spike ADP and limit its duration, thereby precluding its escalation to a burst. Consequently, down-modulation of KCNQ/M channels converts the neuronal firing pattern from simple to complex spiking, whereas up-modulation of these channels exerts the opposite effect.
In many principal brain neurons, the fast, all-or-none Na ϩ spike initiated at the proximal axon is followed by a slow, graded afterdepolarization (ADP). The spike ADP is critically important in determining the firing mode of many neurons; large ADPs cause neurons to fire bursts of spikes rather than solitary spikes. Nonetheless, not much is known about how and where spike ADPs are initiated. We addressed these questions in adult CA1 pyramidal cells, which manifest conspicuous somatic spike ADPs and an associated propensity for bursting, using sharp and patch microelectrode recordings in acutely isolated hippocampal slices and single neurons. Voltage-clamp commands mimicking spike waveforms evoked transient Na ϩ spike currents that declined quickly after the spike but were followed by substantial sustained Na ϩ spike aftercurrents. Drugs that blocked the persistent Na ϩ current (I NaP ), markedly suppressed the sustained Na ϩ spike aftercurrents, as well as spike ADPs and associated bursting. Ca 2ϩ spike aftercurrents were much smaller, and reducing them had no noticeable effect on the spike ADPs. Truncating the apical dendrites affected neither spike ADPs nor the firing modes of these neurons. Application of I NaP blockers to truncated neurons, or their focal application to the somatic region of intact neurons, suppressed spike ADPs and associated bursting, whereas their focal application to distal dendrites did not. We conclude that the somatic spike ADPs are generated predominantly by persistent Na ϩ channels located at or near the soma. Through this action, proximal I NaP critically determines the firing mode and spike output of adult CA1 pyramidal cells.
The generation of high-frequency spike bursts ("complex spikes"), either spontaneously or in response to depolarizing stimuli applied to the soma, is a notable feature in intracellular recordings from hippocampal CA1 pyramidal cells (PCs) in vivo. There is compelling evidence that the bursts are intrinsically generated by summation of large spike afterdepolarizations (ADPs). Using intracellular recordings in adult rat hippocampal slices, we show that intrinsic burst-firing in CA1 PCs is strongly dependent on the extracellular concentration of Ca 2ϩ ([Ca 2ϩ
The input-output relationship of neuronal networks depends both on their synaptic connectivity and on the intrinsic properties of their neuronal elements. In addition to altered synaptic properties, profound changes in intrinsic neuronal properties are observed in many CNS disorders. These changes reflect alterations in the functional properties of dendritic and somatic voltage- and Ca2+-gated ion channels. The molecular mechanisms underlying this intrinsic plasticity comprise the highly specific transcriptional or post-transcriptional regulation of ion-channel expression, trafficking and function. The studies reviewed here show that intrinsic plasticity, in conjunction with synaptic plasticity, can fundamentally alter the input-output properties of neuronal networks in CNS disorders.
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