Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice

Myokymia is characterized by spontaneous, involuntary muscle fiber group contraction visible as vermiform movement of the overlying skin. Myokymia with episodic ataxia is a rare, autosomal dominant trait caused by mutations in KCNA1, encoding a voltage-gated potassium channel. In the present study, we report a family with four members affected with myokymia. Additional clinical features included motor delay initially diagnosed as cerebral palsy, worsening with febrile illness, persistent extensor plantar reflex, and absence of epilepsy or episodic ataxia. Mutation analysis revealed a novel c.676C>A substitution in the potassium channel gene KCNA1, resulting in a T226K nonconservative missense mutation in the Kv1.1 subunit in all affected individuals. Electrophysiological studies of the mutant channel expressed in Xenopus oocytes indicated a loss of function. Co-expression of WT and mutant cRNAs significantly reduced whole-oocyte current compared to expression of WT Kv1.1 alone.

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“…The KCNA1 knockout mouse has been reported to exhibit altered inhibition of layer V pyramidal neocortical neurons [13]. …”

Section: Discussionmentioning

confidence: 99%

Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia

et al. 2006

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“…enhanced excitability through alterations in presynaptic inputs to layer V pyramidal neurons [van Brederode et al, 1998]. …”

Section: Neuronal Activation Is Dependent On Age Genotype and Brain mentioning

confidence: 99%

Developmental Seizure Susceptibility of Kv1.1 Potassium Channel Knockout Mice

Rho

Szot

Tempel³

et al. 1999

Dev Neurosci

108

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Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 α-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (–/–, +/–, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 –/– animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/– mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1.1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.

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“…In parallel, increased GABA release with unaltered glutamatergic transmission in cerebral cortex (van Brederode et al, 2001) was associated with spontaneous seizures in Kv1.1-null mice (Brew et al, 2007;Rho et al, 1999;Smart et al, 1998). Although the Kv1 channels underlying altered GABAergic inhibition are potentially different, both findings are at odds with data showing seizure control following therapeutic enhancement of GABAergic transmission and seizurogenic properties of GABA A R blockade (Burt, 1962;Paul et al, 1979).…”

Section: Potential Role Of Altered Gaba Transmission and Kv1 Channel mentioning

confidence: 99%

Increased Kv1 Channel Expression May Contribute to Decreased sIPSC Frequency Following Chronic Inhibition of NR2B-Containing NMDAR

Shao

Rittase

et al. 2012

Neuropsychopharmacol

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Numerous studies have documented the effects of chronic N-methyl-D-aspartate receptor (NMDAR) blockade on excitatory circuits, but the effects on inhibitory circuitry are not well studied. NR2A- and NR2B-containing NMDARs play differential roles in physiological processes, but the consequences of chronic NR2A- or NR2B-containing NMDAR inhibition on glutamatergic and GABAergic neurotransmission are unknown. We investigated altered GABAergic neurotransmission in dentate granule cells and interneurons following chronic treatment with the NR2B-selective antagonist, Ro25,6981, the NR2A-prefering antagonist, NVP-AAM077, or the non-subunit-selective NMDAR antagonist, D-APV, in organotypic hippocampal slice cultures. Electrophysiological recordings revealed large reductions in spontaneous inhibitory postsynaptic current (sIPSC) frequency in both granule cells and interneurons following chronic Ro25,6981 treatment, which was associated with minimally altered sIPSC amplitude, miniature inhibitory postsynaptic current (mIPSC) frequency, and mIPSC amplitude, suggesting diminished action potential-dependent GABA release. Chronic NVP-AAM077 or D-APV treatment had little effect on these measures. Reduced sIPSC frequency did not arise from downregulated GABA(A)R, altered excitatory or inhibitory drive to interneurons, altered interneuron membrane properties, increased failure rate, decreased action potential-dependent release probability, or mGluR/GABA(B) receptor modulation of GABA release. However, chronic Ro25,6981-mediated reductions in sIPSC frequency were occluded by the K+ channel blockers, dendrotoxin, margatoxin, and agitoxin, but not dendrotoxin-K or XE991. Immunohistochemistry also showed increased Kv1.2, Kv1.3, and Kv1.6 in the dentate molecular layer following chronic Ro25,6981 treatment. Our findings suggest that increased Kv1 channel expression/function contributed to diminished action potential-dependent GABA release following chronic NR2B-containing NMDAR inhibition and that these Kv1 channels may be heteromeric complexes containing Kv1.2, Kv1.3, and Kv1.6.

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Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice

Cited by 26 publications

References 31 publications

Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia

Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia

Developmental Seizure Susceptibility of Kv1.1 Potassium Channel Knockout Mice

Increased Kv1 Channel Expression May Contribute to Decreased sIPSC Frequency Following Chronic Inhibition of NR2B-Containing NMDAR

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