Mutations in the K+/Cl−Cotransporter Genekazachoc(kcc) Increase Seizure Susceptibility inDrosophila
| Autor: | Rakhee Ranga, Mark A. Tanouye, Miriam Y. Lundy, Daria S. Hekmat-Scafe |
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| Rok vydání: | 2006 |
| Předmět: |
Symporters
GABAA receptor General Neuroscience Chromosome Mapping Articles Biology Inhibitory postsynaptic potential medicine.disease Epileptogenesis Epilepsy Drosophila melanogaster Phenotype medicine.anatomical_structure Seizures Mutation Neuropil medicine Excitatory postsynaptic potential Animals GABAergic Genetic Predisposition to Disease Cotransporter Neuroscience gamma-Aminobutyric Acid Signal Transduction |
| Zdroj: | The Journal of Neuroscience. 26:8943-8954 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.4998-05.2006 |
| Popis: | During a critical period in the developing mammalian brain, there is a major switch in the nature of GABAergic transmission from depolarizing and excitatory, the pattern of the neonatal brain, to hyperpolarizing and inhibitory, the pattern of the mature brain. This switch is believed to play a major role in determining neuronal connectivity via activity-dependent mechanisms. The GABAergic developmental switch may also be particularly vulnerable to dysfunction leading to seizure disorders. The developmental GABA switch is mediated primarily by KCC2, a neuronal K+/Cl−cotransporter that determines the intracellular concentration of Cl−and, hence, the reversal potential for GABA. Here, we report thatkazachoc(kcc) mutations that reduce the level of the sole K+/Cl−cotransporter in the fruitflyDrosophila melanogasterrender flies susceptible to epileptic-like seizures.Drosophilakcc protein is widely expressed in brain neuropil, and its level rises with developmental age. Youngkccmutant flies with low kcc levels display behavioral seizures and demonstrate a reduced threshold for seizures induced by electroconvulsive shock. Thekccmutation enhances a series of otherDrosophilaepilepsy mutations indicating functional interactions leading to seizure disorder. Both genetic and pharmacological experiments suggest that the increased seizure susceptibility ofkccflies occurs via excitatory GABAergic signaling. Thekccmutants provide an excellent model system in which to investigate how modulation of GABAergic signaling influences neuronal excitability and epileptogenesis. |
| Databáze: | OpenAIRE |
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