Deficit of Kcnma1 mRNA expression in the dentate gyrus of epileptic rats

Ermolinsky, Boris S.; Arshadmansab, Massoud F.; Otalora, Luis F. Pacheco; Zarei, Masoud; Garrido-Sanabria, Emilio R.

doi:10.1097/wnr.0b013e3283094bb6

Cited by 25 publications

(31 citation statements)

References 22 publications

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“…A gain-of-function of K Ca1.1 currents associated with increased spontaneous and evoked firing rates occurs in mouse neocortical pyramidal neurons 24 h after chemoconvulsant-induced generalized tonic-clonic seizures (Shruti et al, 2008). Conversely, in a model of pilocarpine-induced MTLE K Ca1.1 channel α subunit was down-regulated at the protein and mRNA level in hyppocampal mossy fibers originating from the dentate gyrus (Ermolinsky et al, 2008; Miceli et al, 2013). Notably, K Ca1.1 channel proteins remaining after seizure induction were mostly changed to the STREX splicing isoform, displaying an increased Ca 2+ -sensitivity with respect to the ZERO splice variant normally present (Ermolinsky et al, 2008).…”

Section: Kca11 Channelepsymentioning

confidence: 99%

“…Conversely, in a model of pilocarpine-induced MTLE K Ca1.1 channel α subunit was down-regulated at the protein and mRNA level in hyppocampal mossy fibers originating from the dentate gyrus (Ermolinsky et al, 2008; Miceli et al, 2013). Notably, K Ca1.1 channel proteins remaining after seizure induction were mostly changed to the STREX splicing isoform, displaying an increased Ca 2+ -sensitivity with respect to the ZERO splice variant normally present (Ermolinsky et al, 2008). The functional consequence of the observed changes is thus not clear.…”

Section: Kca11 Channelepsymentioning

confidence: 99%

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K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

D’Adamo

Catacuzzeno

Giovanni

et al. 2013

Front. Cell. Neurosci.

105

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K+ channels are important determinants of seizure susceptibility. These membrane proteins, encoded by more than 70 genes, make the largest group of ion channels that fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their ubiquity and extremely high genetic and functional diversity, unmatched by any other ion channel type, place K+ channels as primary targets of genetic variations or perturbations in K+-dependent homeostasis, even in the absence of a primary channel defect. It is therefore not surprising that numerous inherited or acquired K+ channels dysfunctions have been associated with several neurologic syndromes, including epilepsy, which often generate confusion in the classification of the associated diseases. Therefore, we propose to name the K+ channels defects underlying distinct epilepsies as “K+ channelepsies,” and introduce a new nomenclature (e.g., Kx.y-channelepsy), following the widely used K+ channel classification, which could be also adopted to easily identify other channelopathies involving Na+ (e.g., Navx.y-phenotype), Ca2+ (e.g., Cavx.y-phenotype), and Cl− channels. Furthermore, we discuss novel genetic defects in K+ channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K+ channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets.

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Section: Kca11 Channelepsymentioning

confidence: 99%

Section: Kca11 Channelepsymentioning

confidence: 99%

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

D’Adamo

Catacuzzeno

Giovanni

et al. 2013

Front. Cell. Neurosci.

105

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“…Because BK channels play a critical role in repolarizing the membrane potential after AP firing, loss of BK channel function typically results in increased seizure susceptibility (40,41). In line with loss-of-function mechanisms, pharmacological inhibition of BK channels triggers seizures (42), down-regulation of BK channel expression is associated with the development of temporal lobe epilepsy in rats (43,44), and a particular KCNMB4 SNP is strongly correlated with temporal lobe epilepsy in humans (45). Interestingly, some gain-offunction mutations in BK channels have also been implicated in seizure etiology, primarily absence epilepsy, by rapidly repolarizing the membrane and allowing for faster firing rates (46,47).…”

Section: Discussionmentioning

confidence: 99%

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

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

107

132

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Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre-and postsynaptic defects, yet whether the pre-and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic-and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.F ragile X syndrome (FXS) is the most common single-gene disorder responsible for intellectual disability (ID) in patients (1). Along with cognitive dysfunction, the syndrome typically presents with several other comorbidities, including behavioral and social impairments (anxiety and autism spectrum disorder), neurological defects (seizures and abnormal sleep patterns), and morphological abnormalities (dysmorphic facies and macroorchidism). Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP.FMRP has complex multifaceted functions at synapses both in pre-and postsynaptic compartments. As an RNA binding protein, FMRP is best known for its function as a translation regulator in dendrites (2). Loss of FMRP has been linked to various forms of long-term synaptic plasticity defects that depend on local protein synthesis in the postsynaptic neuron (3). In addition to disrupted metabotropic glutamate receptor signaling, which has been shown across multiple brain regions (4-7), FMRP is necessary for activitydependent protein synthesis downstream of other signaling receptor pathways, including ACh, dopamine, and TrkB (8-10).Although postsynaptic control of translation is believed to be the dominant function of FMRP, it is unable to explain all of the pathophysiology observed in FXS animal models. For instance, in Drosophila, presynaptic expression of the FMR1 homolog, dfmr1, completely rescues the synaptic overgrowth phenotype at the neuromuscular junction (NMJ) in dfmr1-null mutants (11-13). In rodent brain, FMRP has been found in structures called fragile-X granules, which are ...

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“…However, the reduced BK Ca current density was not associated with downegulation of BK Ca channel α-subunit in IC neurons of GEPR-3s [96]; thus, other mechanisms (such as phosphorylation or dephosphorylation of the channel) may account for the reduced current density. In a model of TLE, however, a downregulation of the BK Ca channel α subunits was reported in the cortex and hippocampus (specifically in the mossy fibers), during the active (or chronic) phase of epilepsy [97,98]. Interestingly, BK Ca channels are abundantly expressed at glutamatergic presynaptic terminals including at the mossy fibers where they can control glutamate release under conditions of excessive neuronal activity.…”

Section: Bkca Channelsmentioning

confidence: 99%

Targeting BK (big potassium) channels in epilepsy

N’Gouemo

2011

Expert Opinion on Therapeutic Targets

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Introduction Epilepsies are disorders of neuronal excitability characterized by spontaneous and recurrent seizures. Ion channels are critical for regulating neuronal excitability and, therefore, can contribute significantly to epilepsy pathophysiology. In particular, large conductance, Ca2+-activated K+ (BKCa) channels play an important role in seizure etiology. These channels are activated by both membrane depolarization and increased intracellular Ca2+. This unique coupling of Ca2+ signaling to membrane depolarization is important in controlling neuronal hyperexcitability, as outward K+ current through BKCa channels hyperpolarizes neurons. Areas covered This review focuses on BKCa channel structure-function and discusses the role of these channels in epilepsy pathophysiology. Expert opinion Loss-of-function BKCa channels contribute neuronal hyperexcitability that can lead to temporal lobe epilepsy, tonic-clonic seizures and alcohol withdrawal seizures. Similarly, BKCa channel blockade can trigger seizures and status epilepticus. Paradoxically, some mutations in BKCa channel subunit can give rise to the channel gain-of-function that leads to development of idiopathic epilepsy (primarily absence epilepsy). Seizures themselves also enhance BKCa channel currents associated with neuronal hyperexcitability, and blocking BKCa channels suppresses generalized tonic-clonic seizures. Thus, both loss-of-function and gain-of-function BKCa channels might serve as molecular targets for drugs to suppress certain seizure phenotypes including temporal lobe seizures and absence seizures, respectively.

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Deficit of Kcnma1 mRNA expression in the dentate gyrus of epileptic rats

Cited by 25 publications

References 22 publications

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Targeting BK (big potassium) channels in epilepsy

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