Brenner, R. et al. BK channel beta4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nat. Neurosci. 8, 1752-1759

Stanford University, Palo Alto, California, United States
Nature Neuroscience (Impact Factor: 16.1). 01/2006; 8(12):1752-9. DOI: 10.1038/nn1573
Source: PubMed


Synaptic inhibition within the hippocampus dentate gyrus serves a 'low-pass filtering' function that protects against hyperexcitability that leads to temporal lobe seizures. Here we demonstrate that calcium-activated potassium (BK) channel accessory beta4 subunits serve as key regulators of intrinsic firing properties that contribute to the low-pass filtering function of dentate granule cells. Notably, a critical beta4 subunit function is to preclude BK channels from contributing to membrane repolarization and thereby broaden action potentials. Longer-duration action potentials secondarily recruit SK channels, leading to greater spike frequency adaptation and reduced firing rates. In contrast, granule cells from beta4 knockout mice show a gain-of-function for BK channels that sharpens action potentials and supports higher firing rates. Consistent with breakdown of the dentate filter, beta4 knockouts show distinctive seizures emanating from the temporal cortex, demonstrating a unique nonsynaptic mechanism for gate control of hippocampal synchronization leading to temporal lobe epilepsy.

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    • " type because , depending on the cel - lular conductance environment , increasing a hyperpolarizing current can eventually enhance the network excitability , for example by deinac - tivation of excitatory channels or by supporting inhibitory synchronization that underlies certain epilepsy forms ( McCormick and Contreras , 2001 ; Wickenden , 2002 ; Brenner et al . , 2005 ) . Another important aspect is changed network connectiv - ity during epilepsy . In particular , the imbalance of different forms of inhibition in the CA regions and the subiculum has to be studied carefully when considering the potential impact of intrinsic plas - ticity during TLE ( Cohen et al . , 2002 ; Magloczky and Freund , 2005 "
    Homeostatic Control of Brain Function, Edited by Detlev Boison, Susan A Masino, 10/2015: chapter 4; Oxford University Press., ISBN: 9780199322299
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    • "This effect could arise from enhanced fAHP, which promotes the recovery of Na-channels from inactivation (Klyachko et al., 2001) and may explain the otherwise paradoxical findings that both loss-of-function and gain-of-function mutations in the BK channel  subunit have been associated with seizures (N'Gouemo, 2011). In the present study, we also observed that 4 KO mice per se exhibited faster BK channel gating activity and increased seizure susceptibility, as reported previously (Brenner et al., 2005; Gu et al., 2007). This dual role of BK channels is not unique, however, since gain-of-function mutations in Slack K + channels can lead to epileptic seizures in patients (Kim et al., 2014). "
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    ABSTRACT: Loss of Fragile X Mental Retardation Protein (FMRP) causes Fragile X Syndrome (FXS), yet the mechanisms underlying the pathophysiology of FXS are incompletely understood. Recent studies identified important new functions of FMRP in regulating neural excitability and synaptic transmission via both translation-dependent mechanisms and direct interactions of FMRP with a number of ion channels in the axons and presynaptic terminals. Among these presynaptic FMRP functions, FMRP interaction with BK channels, specifically their auxiliary β4 subunit, regulates action potential waveform and glutamate release in hippocampal and cortical pyramidal neurons. Given the multitude of ion channels and mechanisms that mediate presynaptic FMRP actions, it remains unclear, however, to what extent FMRP-BK channel interactions contribute to synaptic and circuit defects in FXS. To examine this question, we generated Fmr1/β4 double knock-out (dKO) mice to genetically upregulate BK channel activity in the absence of FMRP and determine its ability to normalize multilevel defects caused by FMRP loss. Single-channel analyses revealed that FMRP loss reduced BK channel open probability, and this defect was compensated in dKO mice. Furthermore, dKO mice exhibited normalized action potential duration, glutamate release and short-term dynamics during naturalistic stimulus trains in hippocampal pyramidal neurons. BK channel upregulation was also sufficient to correct excessive seizure susceptibility in an in vitro model of seizure activity in hippocampal slices. Our studies thus suggest that upregulation of BK channel activity normalizes multi-level deficits caused by FMRP loss. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 10/2015; DOI:10.1113/JP271031 · 5.04 Impact Factor
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    • "Finally, despite the hyperpolarizing effect of BK current, studies over the past decade have suggested a role for BK current in promoting repetitive firing and thus potentially opposing spike frequency adaptation, as we proposed in Figure 10. In rodent brain neurons, genetically induced (Brenner et al., 2005) or seizure-induced (Shruti et al., 2008) gain-of-function in BK channels is associated with elevated firing rate. On the other hand, pharmacological block of BK channels reduces firing rate in canine intracardiac neurons (Perez et al., 2013). "
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    ABSTRACT: Temporal patterns of spiking often convey behaviorally relevant information. Various synaptic mechanisms and intrinsic membrane properties can influence neuronal selectivity to temporal patterns of input. However, little is known about how synaptic mechanisms and intrinsic properties together determine the temporal selectivity of neuronal output. We tackled this question by recording from midbrain electrosensory neurons in mormyrid fish, in which the processing of temporal intervals between communication signals can be studied in a reduced in vitro preparation. Mormyrids communicate by varying interpulse intervals (IPIs) between electric pulses. Within the midbrain posterior exterolateral nucleus (ELp), the temporal patterns of afferent spike trains are filtered to establish single-neuron IPI tuning. We performed whole-cell recording from ELp neurons in a whole-brain preparation and examined the relationship between intrinsic excitability and IPI tuning. We found that spike frequency adaptation of ELp neurons was highly variable. Postsynaptic potentials (PSPs) of strongly adapting (phasic) neurons were more sharply tuned to IPIs than weakly adapting (tonic) neurons. Further, the synaptic filtering of IPIs by tonic neurons was more faithfully converted into variation in spiking output, particularly at short IPIs. Pharmacological manipulation under current- and voltage-clamp revealed that tonic firing is mediated by a fast, large-conductance Ca(2+)-activated K(+) (KCa) current (BK) that speeds up action potential repolarization. These results suggest that BK currents can shape the temporal filtering of sensory inputs by modifying both synaptic responses and PSP-to-spike conversion. Slow SK-type KCa currents have previously been implicated in temporal processing. Thus, both fast and slow KCa currents can fine-tune temporal selectivity.
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