KCNQ/M Channels Control Spike Afterdepolarization and Burst Generation in Hippocampal Neurons

Abstract

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.

Study on dynamic characteristics’ change of hippocampal neuron reduced models caused by the Alzheimer’s disease

“…Yue et al found that bursting behavior persists in adult CA1 pyramidal cells after almost complete truncation of the apical dendrites. The bursting mechanism is different from the 'ping-pong' mechanism, which depends on integrity of apical dendrites [25][26][27]. Based on the CA1 pyramidal neuron's membrane ionic channel theory and its electrophysiological experimental data, according to the basic frames of the Hodgkin-Huxley(H-H) class of neuron models, Golomb et al developed the one-compartment model of CA1 pyramidal neuron [5], which is different from the former multi-compartment cable model of the hippocampal pyramid neuron.…”

“…They have studied electrophysiological characteristics of the neuron under the morbid state of AD, and have acquired many research findings and conclusions [15,18,20,22]. Xiaoliang Wang [15] simulated the morbid state of AD by injecting the aggregated Aβ [25][26][27][28][29][30][31][32][33][34][35] into the lateral ventricle. They recorded and studied the electrophysiological characteristics' change of the hippocampal pyramid neuron's voltage-gated currents (the A-type instantaneous K + current (I A ) and the delay rectification K + current (I Kdr )) under the morbid state of AD.…”

“…(1) The aggregated Aβ [25][26][27][28][29][30][31][32][33][34][35] 's injecting into the lateral ventricle in one shot has some effect on the amplitude and the density of A-type instantaneous K + current (I A ). But from the neurodynamics angle, A-type instantaneous K + current's stable activation dynamic characteristics and stable inactivation dynamic characteristics have no significant difference [15].…”

“…But from the neurodynamics angle, A-type instantaneous K + current's stable activation dynamic characteristics and stable inactivation dynamic characteristics have no significant difference [15]. (2) The aggregated Aβ [25][26][27][28][29][30][31][32][33][34][35] 's injecting into the lateral ventricle in one shot has great effect on the amplitude and the density of the delay rectification K + current (I Kdr ).…”

“…The existing findings have proved that AD can cause electrophysiological characteristics' change of the hippocampal neuron, and especially can cause change of the potassium ion channel characteristics [1,18,21]. Dependent on electrophysiological experiments and new technologies, such as optics imaging, some models of hippocampal pyramidal neurons based on ionic conductance have been successfully constructed [3,4,5,6,9,[11][12][13][14]19,[23][24][25][26][27].…”