Kv4.2 knockout mice demonstrate increased susceptibility to convulsant stimulation

Barnwell, Lyndon F.; Lugo, Joaquín N.; Lee, Wai Ling; Willis, Stephen M.; Gertz, Shira J.; Hrachovy, Richard A.; Anderson, Anne E.

doi:10.1111/j.1528-1167.2009.02086.x

Cited by 68 publications

(64 citation statements)

References 42 publications

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“…3). This pattern of evolution of electrographic activity is comparable with that described for other chemoconvulsants, e.g., kainate or 4-aminopyridine, but ictal events appear much later after administration of AG [65,66].…”

Section: Electrographic Brain Activity In Ag-treated Micesupporting

confidence: 83%

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be timeconsuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (D,L)-Allylglycine inhibits glutamic acid decarboxylase (GAD) -the key enzyme in γ-aminobutyric acid (GABA) biosynthesis -leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD 50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated crossspecies similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

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Section: Electrographic Brain Activity In Ag-treated Micesupporting

confidence: 83%

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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“…Moreover, the role of I A in regulating neuronal excitability has been underscored by the demonstration that development of temporal lobe epilepsy is associated with decreased I A through transcriptional down-regulation of Kv4.2 and increased Kv4.2 phosphorylation by ERK (7) and that Kv4.2 Ϫ/Ϫ mice show an increased susceptibility to seizures after injection of kainate (19). Although these studies highlighted the essential nature of Kv4.2, the specific contributions of its auxiliary KChIP subunits were less clear.…”

Section: Discussionmentioning

confidence: 99%

The Auxiliary Subunit KChIP2 Is an Essential Regulator of Homeostatic Excitability

Wang

et al. 2013

Journal of Biological Chemistry

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Background:The necessity for, or redundancy of, distinctive KChIP proteins is not known. Results: Deletion of KChIP2 leads to increased susceptibility to epilepsy and to a reduction in I A and increased excitability in pyramidal hippocampal neurons. Conclusion: KChIP2 is essential for homeostasis in hippocampal neurons. Significance: Mutations in K ϩ channel auxiliary subunits may be loci for epilepsy.

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“…Furthermore, Kv4.2 expression and phosphorylation is altered in animal models of temporal lobe epilepsy in both the acute (Lugo et al 2008) and chronic (Bernard et al 2004) phases. While Kv4.2 KO mice do not have unprovoked seizures or epilepsy, they have an increased susceptibility to chemoconvulsantinduced seizures (Barnwell et al 2009). These previous studies suggest that a reduction in the levels of functional Kv4.2 channels is involved in the development of epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…The mice began behavioral testing on approximately post-natal day 90. Genotyping of littermates was performed by PCR using Kv4.2-specific primers as previously described (Barnwell et al 2009). …”

Section: Animalsmentioning

confidence: 99%

Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits

Lugo

Brewster²,

Spencer³

et al. 2012

Learn. Mem.

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Kv4.2 channels contribute to the transient, outward K + current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit in the learning phase of the Morris water maze (MWM) and significant impairment in the probe trial compared with wild type (WT). Kv4.2 KO mice also demonstrated a specific deficit in contextual learning in the fear-conditioning test, without impairment in the conditioned stimulus or new context condition. Kv4.2 KO mice had normal activity, anxiety levels, and prepulse inhibition compared with WT mice. A compensatory increase in tonic inhibition has been previously described in hippocampal slice recordings from Kv4.2 KO mice. In an attempt to decipher whether increased tonic inhibition contributed to the learning and memory deficits in Kv4.2 KO mice, we administered picrotoxin to block GABA A receptors (GABA A R), and thereby tonic inhibition. This manipulation had no effect on behavior in the WT or KO mice. Furthermore, total protein levels of the a5 or d GABA A R subunits, which contribute to tonic inhibition, were unchanged in hippocampus. Overall, our findings add to the growing body of evidence, suggesting an important role for Kv4.2 channels in hippocampal-dependent learning and memory.Potassium (K + ) channels within hippocampal dendrites are critical regulators of post-synaptic excitability and thereby contribute to the modulation of synaptic plasticity . In particular, the transient, rapidly activating K + current (A-type current) modulates neuronal excitability by attenuating action potential initiation and back-propagating action potentials (B-APs), which reduce excitatory synaptic events (Hoffman et al. 1997;Martina et al. 1998;Johnston et al. 2000;Cai et al. 2004). The primary mediator of the A-type current in the somatodendritic regions of hippocampal pyramidal cells are the Kv4.X-subunits, and genetic deletion of Kv4.2 channels nearly eliminates the A-type current in CA1 pyramidal cell dendrites . The localization and function of Kv4.2 channels support a role for these channels in modulating synaptic activity in the hippocampus and influencing hippocampal-dependent tasks.Kv4.2 channel proteins localize to the somatodendritic regions of hippocampal principal neurons (Baldwin et al. 1991;Sheng et al. 1992;Maletic-Savatic et al. 1995;Martina et al. 1998; Serodio and Rudy 1998), and their highest expression is found in area CA1 pyramidal cell dendrites (Rhodes et al. 2004). These channel proteins localize to dendritic spines, where their activity can be modulated through auxiliary subunits and through a number of kinases. For example, activation of PKA, PKC, and ERK can down-regulate the activity and surface expression of Kv4.2 channels, which can then increase excitability within distal dendrites of CA1 neurons (for review, see Birnbaum et al. 2004).Furthermore, alteratio...

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Kv4.2 knockout mice demonstrate increased susceptibility to convulsant stimulation

Cited by 68 publications

References 42 publications

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

The Auxiliary Subunit KChIP2 Is an Essential Regulator of Homeostatic Excitability

Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits

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