title: Critical role of canonical transient receptor potential channel 7 in initiation of seizures.
abstract: Status epilepticus (SE) is a life-threatening disease that has been recognized since antiquity but still causes over 50,000 deaths annually in the United States. The prevailing view on the pathophysiology of SE is that it is sustained by a loss of normal inhibitory mechanisms of neuronal activity. However, the early process leading to the initiation of SE is not well understood. Here, we show that, as seen in electroencephalograms, SE induced by the muscarinic agonist pilocarpine in mice is preceded by a specific increase in the gamma wave, and genetic ablation of canonical transient receptor potential channel (TRPC) 7 significantly reduces this pilocarpine-induced increase of gamma wave activity, preventing the occurrence of SE. At the cellular level, TRPC7 plays a critical role in the generation of spontaneous epileptiform burst firing in cornu ammonis (CA) 3 pyramidal neurons in brain slices. At the synaptic level, TRPC7 plays a significant role in the long-term potentiation at the CA3 recurrent collateral synapses and Schaffer collateral-CA1 synapses, but not at the mossy fiber-CA3 synapses. Taken together, our data suggest that epileptiform burst firing generated in the CA3 region by activity-dependent enhancement of recurrent collateral synapses may be an early event in the initiation process of SE and that TRPC7 plays a critical role in this cellular event. Our findings reveal that TRPC7 is intimately involved in the initiation of seizures both in vitro and in vivo. To our knowledge, this contribution to initiation of seizures is the first identified functional role for the TRPC7 ion channel.
authors: Departments of Neurobiology and Developmental Sciences and.
authors: Kevin D
authors: KD
authors: Phelan
authors: Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205; and.
authors: U Thaung
authors: UT
authors: Shwe
authors: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
authors: Joel
authors: J
authors: Abramowitz
authors: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 birnbau1@niehs.nih.gov zhengfang@uams.edu.
authors: Lutz
authors: L
authors: Birnbaumer
authors: Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205; and birnbau1@niehs.nih.gov zhengfang@uams.edu.
authors: Fang
authors: F
authors: Zheng
mesh_terms: D000200:Action Potentials; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004558:Electric Stimulation; D004569:Electroencephalography; D017774:Long-Term Potentiation; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D010862:Pilocarpine; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: D018094:Receptors, Metabotropic Glutamate; D050052:TRPC Cation Channels; C498502:Trpc7 protein, mouse; D010862:Pilocarpine
keywords: epilepsy; gamma oscillation; hippocampal circuitry; synaptic plasticity