Loss of the Kv1.1 potassium channel promotes pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices

NEUROBIOLOGY OF DISEASE

卷:54

Article

Simeone, Timothy A.^1,2  Simeone, Kristina A.^1,2  Samson, Kaeli K.¹  Kim, Do Young²  Rho, Jong M.^2,3,4 

[1] Creighton Univ, Dept Pharmacol, Omaha, NE 68174 USA

[2] St Josephs Med Ctr, Barrow Neurol Inst, Phoenix, AZ 85013 USA

[3] Univ Calgary, Alberta Childrens Hosp, Fac Med, Dept Paediat, Calgary, AB T3B 6A8, Canada

[4] Univ Calgary, Alberta Childrens Hosp, Fac Med, Dept Clin Neurosci, Calgary, AB T3B 6A8, Canada

关键词: High frequency oscillation;    Epilepsy;    Potassium channel;    Sharp wave;    Hippocampus;    K(v)1.1;    Multielectrode array;    Ripple;    Fast ripple;    Channelopathy;   

DOI  :  10.1016/j.nbd.2013.02.009

来源: Elsevier

【 摘 要 】

In human disease, channelopathies involving functional reduction of the delayed rectifier potassium channel alpha-subunit K(v)1.1 - either by mutation or autoimmune inhibition - result in temporal lobe epilepsy. K(v)1.1 is prominently expressed in the axons of the hippocampal tri-synaptic pathway, suggesting its absence will result in widespread effects on normal network oscillatory activity. Here, we performed in vitro extracellular recordings using a multielectrode array to determine the effects of loss of K(v)1.1 on spontaneous sharp waves (SPWs) and high frequency oscillations (HFOs). We found that Kcna1-null hippocampi generate SPWs and ripples (80-200 Hz bandwidth) with a 50% increased rate of incidence and 50% longer duration, and that epilepsy-associated pathologic HFOs in the fast ripple bandwidth (200-600 Hz) are also present. Furthermore, Kcna1-null CA3 has enhanced coupling of excitatory inputs and population spike generation and CA3 principal cells have reduced spike timing reliability. Removing the influence of mossy fiber and perforant path inputs by micro-dissecting the Kcna1-null CA3 region mostly rescued the oscillatory behavior and improved spike timing. We found that Kcna1-null mossy fibers and medial perforant path axons are hyperexcitable and produce greater pre- and post-synaptic responses with reduced paired-pulse ratios suggesting increased neurotransmitter release at these terminals. These findings were recapitulated in wild-type slices exposed to the K(v)1.1 inhibitor dendrotoxin-kappa. Collectively, these data indicate that loss of K(v)1.1 enhances synaptic release in the CA3 region, which reduces spike timing precision of individual neurons leading to disorganization of network oscillatory activity and promotes the emergence of fast ripples. (C) 2013 Elsevier Inc. All rights reserved.

【 授权许可】

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