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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

ABSTRACT

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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    • "BK current properties are modulated by several nonobligatory b (b1–4) and c accessory subunits (c1–4) (Brenner et al. 2000a; Yan and Aldrich 2012), tuning current properties for diverse roles across a variety of tissues. In rodents, BK channels are found in brain (Tseng-Crank et al. 1994; Kang et al. 1996; Smith et al. 2002; Faber and Sah 2003; Sausbier et al. 2004; Brenner et al. 2005; Girouard et al. 2010), peripheral neurons (Scholz et al. 1998; Ramanathan et al. 1999), muscle (Tseng-Crank et al. 1994; McCobb et al. 1995; Nelson et al. 1995; Heppner et al. 1997), and nonexcitable cells such as glia, kidney, bone, and endothelium (Morita et al. 1997; Papassotiriou et al. 2000; Ransom and Sontheimer 2001; Filosa et al. 2006; Henney et al. 2009; Li et al. 2009). Despite the ubiquity of BK currents, mice carrying targeted mutations in the BK channel pore-forming a subunit, which do not produce functional BK currents , are viable (Meredith et al. 2004; Sausbier et al. 2004). "
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    ABSTRACT: BK large conductance calcium-activated K(+) channels (KC a1.1) are expressed widely across many tissues, contributing to systemic regulation of cardiovascular, neurological, and other specialized physiological functions. The pore-forming α subunit is encoded by the Kcnma1 gene, originally named mSlo1 in mouse and slowpoke in Drosophila. Global deletion in mouse (Kcnma1(-/-)) produces a plethora of defects in neuron and muscle excitability, as well as other phenotypes related to channel function in nonexcitable cells. While homozygous null mice are viable, the ubiquitous loss of BK function has complicated the interpretation of phenotypes involving the interaction of multiple cell types which independently express BK channels. Here, we report the generation of a targeted allele for conditional inactivation of Kcnma1 using the Cre-loxP system (Kcnma1(fl)-tdTomato). Cre-mediated recombination generates a null allele, and BK currents were not detectable in neurons and muscle cells from Nestin-Cre; Kcnma1(fl/fl) and SM22α-Cre; Kcnma1(fl/fl) mice, respectively. tdTomato expression was detected in Cre-expressing tissues, but not in Cre-negative controls. These data demonstrate the utility of Kcnma1(fl)-tdTomato for conditional deletion of the BK channel, facilitating the understanding of tissue-specific contributions to physiological function in vivo.
    Full-text · Article · Nov 2015
    • " 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 "

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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 large-conductance calcium-activated K+ (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 knockout (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.
    Full-text · Article · Oct 2015 · The Journal of Physiology
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