Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Altered ion channel expression and/or function may contribute to the development of certain human epilepsies. In rats, systemic administration of pilocarpine induces a model of human temporal lobe epilepsy, wherein a brief period of status epilepticus (SE) triggers development of spontaneous recurrent seizures that appear after a latency of 2-3 weeks. Here we investigate changes in expression of A-type voltage-gated potassium (Kv) channels, which control neuronal excitability and regulate action potential propagation and neurotransmitter release, in the pilocarpine model of epilepsy. Using immunohistochemistry, we examined the expression of component subunits of somatodendritic (Kv4.2, Kv4.3, KChIPl and KChIP2) and axonal (Kv1.4) A-type Kv channels in hippocampi of pilocarpine-treated rats that entered SE. We found that Kv4.2, Kv4.3 and KChIP2 staining in the molecular layer of the dentate gyrus changes from being uniformly distributed across the molecular layer to concentrated in just the outer two-thirds. We also observed a loss of KChIP1 immunoreactive interneurons, and a reduction of Kv4.2 and KChIP2 staining in stratum radiatum of CA1. These changes begin to appear 1 week after pilocarpine treatment and persist or are enhanced at 4 and 12 weeks. As such, these changes in Kv channel distribution parallel the acquisition of recurrent spontaneous seizures as observed in this model. We also found temporal changes in Kv1.4 immunoreactivity matching those in Timm's stain, being expanded in stratum lucidum of CA3 and in the inner third of the dentate molecular layer. Among pilocarpine-treated rats, changes were only observed in those that entered SE. These changes in A-type Kv channel expression may contribute to hyperexcitability of dendrites in the associated hippocampal circuits as observed in previous studies of the effects of pilocarpine-induced SE.
 ...
PMID:Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy. 1872 53

Compelling evidences from transgenic mice, immunoprecipitation data, gene expression analysis, and functional heterologous expression studies supported the role of Kv channel interacting proteins (KChIPs) as modulators of Kv4 (Shal) channels underlying the cardiac transient outward current and neuronal A-type current. Till now, there are four members (KChIP1-4) identified in this family. KChIP1 is expressed predominantly in brain, with relative abundance in Purkinje cells of cerebellum, the reticular thalamic nuclei, the medial habenular nuclei, the hippocampus, and striatum. Our results from in situ hybridization and immunostaining assay revealed that KChIP1 was expressed in a subpopulation of parvalbumin-positive neurons suggesting its functional relationship with the GABAergic inhibitory neurons. Moreover, results obtained from KChIP1-deficient mice showed that KChIP1 mutation did not impair survival or alter the overall brain architecture, arguing against its essential function in brain development. However, the mice bearing KChIP1 deletion showed increased susceptibility to anti-GABAergic convulsive drug pentylenetetrazole-induced seizure, indicating that KChIP1 might play pivotal roles in the GABAergic inhibitory system.
 ...
PMID:KChIP1: a potential modulator to GABAergic system. 1935 44

Sudden unexpected death in epilepsy (SUDEP) is among the leading causes of death in people with epilepsy. Individuals with temporal lobe epilepsy (TLE) have a high risk for SUDEP because the seizures are often medically intractable. Neurons in the nucleus tractus solitarii (NTS) have been implicated in mouse models of SUDEP and play a critical role in modulating cardiorespiratory and autonomic output. Increased neuronal excitability of inhibitory, GABAergic neurons in the NTS develops during epileptogenesis, and NTS dysfunction has been implicated in mouse models of SUDEP. In this study we used the pilocarpine-induced status epilepticus model of TLE (i.e., pilo-SE mice) to investigate the A-type voltage-gated K+ channel as a potential contributor to increased excitability in GABAergic NTS neurons during epileptogenesis. Compared with age-matched control mice, pilo-SE mice displayed an increase in spontaneous action potential frequency and half-width 9-12 wk after treatment. Activity of GABAergic NTS neurons from pilo-SE mice showed less sensitivity to 4-aminopyridine. Correspondingly, reduced A-type K+ current amplitude was detected in these neurons, with no change in activation or inactivation kinetics. No changes were observed in Kv4.1, Kv4.2, Kv4.3, KChIP1, KChIP3, or KChIP4 mRNA expression. These changes contribute to the increased excitability in GABAergic NTS neurons that develops in TLE and may provide insight into potential mechanisms contributing to the increased risk for cardiorespiratory collapse and SUDEP in this model. NEW & NOTEWORTHY Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in epilepsy, and dysfunction in central autonomic neurons may play a role. In a mouse model of acquired epilepsy, GABAergic neurons in the nucleus tractus solitarii developed a reduced amplitude of the A-type current, which contributes to the increased excitability seen in these neurons during epileptogenesis. Neuronal excitability changes in inhibitory central vagal circuitry may increase the risk for cardiorespiratory collapse and SUDEP.
 ...
PMID:Altered A-type potassium channel function in the nucleus tractus solitarii in acquired temporal lobe epilepsy. 3051 61