Deletion of the KV1.1 Potassium Channel Causes Epilepsy in Mice

Smart, Sharon L.; Lopantsev, Valeri; Zhang, C.L.; Robbins, Carol A.; Wang, Hao; Chiu, Shing Yan; Schwartzkroin, Philip A.; Messing, Albee; Tempel, Bruce L.

doi:10.1016/s0896-6273(00)81018-1

Cited by 540 publications

(499 citation statements)

References 63 publications

(34 reference statements)

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“…To monitor spontaneous tonic-clonic seizures, we performed prolonged video EEG starting around P32, or Ϸ30 DAT (see Materials and Methods for full description of electrographic phenotypes). As expected (14,16,17), the EEG of Kv1.1 Ϫ/Ϫ mice showed generalized electrographic seizures lasting between 10 and 340 seconds and occurring approximately once per hour (Fig. 6A).…”

Section: Suppression Of Spontaneous Seizures After Mge Cell Graftingsupporting

confidence: 77%

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

Baraban

Southwell

Estrada

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

200

259

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Epilepsy, a disease characterized by abnormal brain activity, is a disabling and potentially life-threatening condition for nearly 1% of the world population. Unfortunately, modulation of brain excitability using available antiepileptic drugs can have serious side effects, especially in the developing brain, and some patients can only be improved by surgical removal of brain regions containing the seizure focus. Here, we show that bilateral transplantation of precursor cells from the embryonic medial ganglionic eminence (MGE) into early postnatal neocortex generates mature GABAergic interneurons in the host brain. In mice receiving MGE cell grafts, GABA-mediated synaptic and extrasynaptic inhibition onto host brain pyramidal neurons is significantly increased. Bilateral MGE cell grafts in epileptic mice lacking a Shaker-like potassium channel (a gene mutated in one form of human epilepsy) resulted in significant reductions in the duration and frequency of spontaneous electrographic seizures. Our findings suggest that MGE-derived interneurons could be used to ameliorate abnormal excitability and possibly act as an effective strategy in the treatment of epilepsy.epilepsy ͉ inhibition ͉ neocortex ͉ therapy ͉ graft

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Section: Suppression Of Spontaneous Seizures After Mge Cell Graftingsupporting

confidence: 77%

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

Baraban

Southwell

Estrada

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

200

259

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“…Also identified was 14-3-3, a known binding partner of ADAM22 (14). Interestingly, each targeted disruption of ADAM22 (11), ADAM23 (12,15), and Kv 1 channel (Kv 1.1 (16) and Kv 1.2 (17), which form heterotetramer in the brain) causes a similar epileptic phenotype (generalized tonic-clonic seizures beginning around the postnatal second or third week) and premature death in mice, suggesting that LGI1, ADAM22, ADAM23, and Kv 1 channel are genetically associated and functionally related.…”

Section: Resultsmentioning

confidence: 99%

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Fukata¹,

Lovero

Iwanaga³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

295

392

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Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1 −/− ) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1 +/− ) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.A ffecting 1-2% of the population, epilepsy is one of the most common neurological disorders. Epilepsy is characterized by recurrent unprovoked seizures and is caused by disturbances in the delicate balance between excitation and inhibition in neural circuits (1, 2). Recent human genetic studies have established the channelopathy concept for idiopathic (inherited) epilepsies: Many of the genes whose mutations cause human epilepsy encode ion channel subunits (1, 2). Examples include voltagegated ion channels (K + , Na + , Ca 2+ , and Cl -channels) and ligandgated ion channels (nicotinic acetylcholine and GABA A receptors), which regulate neuronal excitability.Leucine-rich glioma inactivated 1 (LGI1) is a unique human epilepsy-related gene in that it does not encode an ion channel subunit (3-5), but is a neuronal secreted protein (6). Mutations in LGI1 are linked to autosomal dominant partial epilepsy with auditory features (ADPEAF, also known as autosomal dominant lateral temporal lobe epilepsy [ADLTE]) (3-5), which is an inherited epileptic syndrome characterized by partial seizures with acoustic or visual hallucinations. So far, 25 LGI1 mutations have been described in familial ADPEAF patients and sporadic cases (7). Interestingly, at least six tested ADPEAF mutations all abolish LGI1 secretion (6,8).Recent proteomic analysis identified LGI1 as a subunit of presynaptic Kv 1 (shaker type)-voltage gated potassium channels (9). It was shown that LGI1 selectively prevents inactivation of the Kv 1 channel mediated by a cytoplasmic regulatory protein, Kvβ. Because LGI1 is a secreted protein, it remains unclear how LGI1 modulates a cytosolic potassium channel mechanism. LGI1 was also isolated from the brain as a component of a protein complex mediated by PSD-95, a representative postsynaptic scaffolding protein.LGI1 functions as a ligand for the epilepsy-related ADAM22 transmembrane protein, which is anchored by PS...

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“…In support of this postulate is the fact that pharmacological manipulations of neuronal excitability (e.g., blockade of IPSCs or neuronal after-spike repolarization) readily result in epileptic-like discharge. Similarly, "knock-out" mutants lacking neuronal voltage-dependent channels exhibit an "epileptic" phenotype (Smart et al, 1998). However, the possibility that non-neuronal ion channel/transporter mutations (i.e., in glia) are linked to epilepsy is supported by an increasing body of experimental evidence (Bennett et al, 1995;Lee et al, 1995;Schwartzkroin et al, 1998;Janigro, 1999).…”

Section: Discussionmentioning

confidence: 99%

Do Glia Have Heart? Expression and Functional Role forEther-A-Go-GoCurrents in Hippocampal Astrocytes

et al. 2000

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Potassium homeostasis plays an important role in the control of neuronal excitability, and diminished buffering of extracellular K results in neuronal Hyperexcitability and abnormal synchronization. Astrocytes are the cellular elements primarily involved in this process. Potassium uptake into astrocytes occurs, at least in part, through voltage-dependent channels, but the exact mechanisms involved are not fully understood. Although most glial recordings reveal expression of inward rectifier currents (K IR ), it is not clear how spatial buffering consisting of accumulation and release of potassium may be mediated by exclusively inward potassium fluxes. We hypothesized that a combination of inward and outward rectifiers cooperate in the process of spatial buffering. Given the pharmacological properties of potassium homeostasis (sensitivity to Cs ϩ ), members of the ether-a-go-go (ERG) channel family widely expressed in the nervous system could underlie part of the process. We used electrophysiological recordings and pharmacological manipulations to demonstrate the expression of ERG-type currents in cultured and in situ hippocampal astrocytes. Specific ERG blockers (dofetilide and E 4031) inhibited hyperpolarizationand depolarization-activated glial currents, and ERG blockade impaired clearance of extracellular potassium with little direct effect on hippocampal neuron excitability. Immunocytochemical analysis revealed ERG protein mostly confined to astrocytes; ERG immunoreactivity was absent in presynaptic and postsynaptic elements, but pronounced in glia surrounding the synaptic cleft. Oligodendroglia did not reveal ERG immunoreactivity. Intense immunoreactivity was also found in perivascular astrocytic end feet at the blood-brain barrier. cDNA amplification showed that cortical astrocytes selectively express HERG1, but not HERG2-3 genes. This study provides insight into a possible physiological role of hippocampal ERG channels and links activation of ERG to control of potassium homeostasis.

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Deletion of the KV1.1 Potassium Channel Causes Epilepsy in Mice

Cited by 540 publications

References 63 publications

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Do Glia Have Heart? Expression and Functional Role forEther-A-Go-GoCurrents in Hippocampal Astrocytes

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