All patients had seizures of presumed temporal lobe origin and no evidence of a secondary lesion that may have contributed to seizures.
Correspondingly, AMPA-subtype ionotropic glutamate receptors, which mediate the majority of excitatory neurotransmission and contribute to seizure generation and spread, have emerged as promising targets for epilepsy therapy.
The results of our experimental study support the hypothesis that inflammatory mechanisms and BBB damage could contribute to seizure generation and severity [40], [41].
Synaptic reorganization is hypothesized to contribute to seizure susceptibility, but the new connections also may represent a potential target for attenuating activity, which is unique to the reorganized circuit.
However, loss-of-function of Nav1.6 may contribute to seizure susceptibility in certain genetic contexts.
Surprisingly, reduced LETM1 expression has not previously been consistently and unequivocally demonstrated in WHS-patient-derived cells despite LETM1 haploinsufficiency being proposed to contribute to seizure development in this condition (Dimmer et al., 2008; Hasegawa and van der Bliek, 2007).
Haploinsufficiency of LETM1, which encodes the mitochondrial protein leucine-zipper EF-hand-containing transmembrane protein 1 (LETM1), is thought to contribute to seizure development in WHS (Dimmer et al., 2008; Endele et al., 1999; Hasegawa and van der Bliek, 2007; McQuibban et al., 2010; Nowikovsky et al., 2004; Tamai et al., 2008).
Mindful of the fact that other genes are also deleted in our WHS lines and that other regions within 4p16.3 might also contribute to seizure development in this condition, we set out to establish whether reduced expression of LETM1 alone could recapitulate some of the key mitochondrial phenotypes that we have identified here.
