Abstract
Paradoxical seizure exacerbation by anti-epileptic medication is a well-known clinical phenomenon in epilepsy, but the cellular mechanisms remain unclear. One possibility is enhanced network disinhibition by unintended suppression of inhibitory interneurons. We investigated this hypothesis in the stargazer mouse model of absence epilepsy, which bears a mutation in stargazin, an AMPA receptor trafficking protein. If AMPA signaling onto inhibitory GABAergic neurons is impaired, their activation by glutamate depends critically upon NMDA receptors. Indeed, we find that stargazer seizures are exacerbated by NMDA receptor blockade with CPP (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid) and MK-801, whereas other genetic absence epilepsy models are sensitive to these antagonists. To determine how an AMPA receptor trafficking defect could lead to paradoxical network activation, we analyzed stargazin and AMPA receptor localization and found that stargazin is detected exclusively in parvalbumin-positive (PV +) fast-spiking interneurons in somatosensory cortex, where it is co-expressed with the AMPA receptor subunit GluA4. PV + cortical interneurons in stargazer show a near twofold decrease in the dendrite:soma GluA4 expression ratio compared to wild-type (WT) littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg 2 +-induced network discharges in WT but augmented bursting in stargazer cortex. Interneurons mediate this paradoxical response, since the difference between genotypes was masked by GABA receptor blockade. Our findings provide a cellular locus for AMPA receptor-dependent signaling defects in stargazer cortex and define an interneuron-dependent mechanism for paradoxical seizure exacerbation in absence epilepsy.
Highlights
The ability of an anti-epileptic drug (AED) to aggravate seizures is an unwelcome clinical problem affecting a small percentage of individuals with epilepsy (Gayatri and Livingston, 2006)
We identified a glutamate-related paradoxical response in the stargazer mouse model of absence epilepsy, where seizures are markedly exacerbated by 3-[(R)-2-carboxypiperazin-4-yl]-prop2-enyl-1-phosphonic acid (CPP), a competitive NMDA receptor antagonist (Nahm and Noebels, 1998), which has been noted to aggravate seizures in some patients with epilepsy (Sveinbjornsdottir et al, 1993)
To determine whether exacerbation by NMDA blockade was specific to the stargazer mutant, a second model of absence epilepsy, tottering mice, which bear a mutation in Cacna1a voltage gated P/Q calcium channels, were injected with 0.5 mg/kg MK-801
Summary
The ability of an anti-epileptic drug (AED) to aggravate seizures is an unwelcome clinical problem affecting a small percentage of individuals with epilepsy (Gayatri and Livingston, 2006). Recent analysis of haploinsufficient Scn1a mouse mutants found a decreased density of inward sodium current that preferentially impaired high frequency discharges in interneurons (Yu et al., 2006; Ogiwara et al, 2007; Dutton et al, 2012) Further depression of their excitability by sodium channel blocking drugs such as phenytoin could synaptically disinhibit pyramidal cells, despite phenytoin’s simultaneous membrane suppressant effects on them. This example of malignant disinhibition arising from an inherently weakened interneuron population identifies a general mechanism for seizure exacerbation by otherwise potent anti-convulsant drugs
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