Developing more effective seizure therapies requires more selective drugs

Abstract

Epilepsy affects more than 50 million people worldwide. Fortunately, anti-epileptic drugs (AEDs) are now available that can, in many cases, prevent the seizures associated with these devastating neurological conditions. However, there is known to be significant individual variability in AED potency, suggesting the presence of important disease modifiers within the population that can render available AED treatments ineffective. Also, the side effects associated with many of the currently available AEDs can negatively impact upon a sufferer’s quality of life. For example, benzodiazepines, the most widely prescribed AEDs, cause drowsiness and impaired coordination, with prolonged use leading to tolerance and addiction. Benzodiazepines dampen neuronal excitability in the brain due to their ability to act as positive allosteric modulators of GABAA receptors (Olsen, 2015). While the sedative, addictive and motor effects of benzodiazepines appear to be mediated through modulatory actions on α1 subunit-containing GABAA receptors, anxiolysis and analgesia are thought to be due to drug binding to sites on α2 and α3 subunit-containing GABAA receptors (Low et al. 2000). It is the heterogeneity of the GABAA receptor family that could offer potential for developing new AEDs that target more specific neuronal networks, thus avoiding many of the known side-effects. Moreover, differences in the expression of GABAA receptor types could in themselves offer some explanation for individual sensitivity to AEDs within the population. In this edition of The Journal of Physiology, Nomura et al. (2019) explore the importance of α2 subunit-containing GABAA receptors in determining seizure severity in a mouse model of Dravet syndrome. Dravet syndrome (DS) is a severe myoclonic infant-onset epilepsy that, in 80% of sufferers, results from a loss-of-function mutation in the SCN1A gene which encodes for the voltage-gated sodium channel NaV 1.1. Impaired NaV 1.1 function in inhibitory interneurons is believed to tip the excitation/inhibition balance in the brain towards a more seizure-prone phenotype. The severity of this seizure phenotype, however, seems to be dramatically influenced by disease modifier genes, including the α2 subunit of the GABAA receptor. Confirming the effect of comparably lower α2 receptor levels, it has previously been shown that Scn1a+/− mice bred on the C57BL/6J background develop more severe epileptic phenotypes compared to those bred on the 129S6/SvEvTac background (Miller et al. 2014). Therefore, Nomura et al. examined the actions of AZD7325, a positive allosteric modulator of α2 and α3 subunit-containing GABAA receptors, in three different strains of mice that were characterised by different levels of the α2 subunit expression: congenic C57BL/6J mice, congenic 129S6/SvEvTac mice, and F1 hybrid C57BL/6J × 129S6/SvEvTac mice. Whole-cell voltage-clamp recordings in acute slice preparations of the hippocampus were used to examine the modulation of native GABAA receptors by AZD7325. Hyperthermia-induced seizure activity was assayed in vivo and behavioural experiments were also performed to look for differences in the sedative properties of this AED candidate between different mouse strains. Nomura et al. showed that AZD7325 increased the decay of miniature inhibitory postsynaptic currents (IPSCs) recorded from CA1 pyramidal cells more potently in recordings from the 129S6/SvEvTac strain compared to recordings from the wild-type F1 hybrid and C57BL/6J mice. This result provides valuable additional insight into the role of disease modifier genes in genetic epilepsies that might explain differences in both disease manifestation and the response to certain anti-seizure medications. By stimulating specific inputs onto CA1 neurons, the authors also examined the effect of AZD7325 on two distinct inhibitory synaptic inputs in the hippocampus – perisomatic α2/α3-rich synapses and more distally located, α1-expressing synapses. While evoked IPSCs at distal synapses remained unaffected, the decay of perisomatically evoked IPSCs was prolonged, providing further functional evidence for the subunit selectivity of AZD7325. This drug was also shown to have a significant protective effect against hyperthermia-induced seizures in the F1 strain consistent with its role as an AED. These results further demonstrate the utility of developing α2 subunit selective compounds as candidates for future AEDs. Another advantage of using an α2 GABAA receptor selective AED would come from its predicted lack of hypnotic side-effects, which could have a significant impact upon quality of life for epilepsy sufferers. In view of the sedative effects of currently used AEDs, the authors compared naive mice with AZD7325-treated mice in an open field test. Intriguingly, neither total distance travelled, nor time spent in the centre of the arena differed between the two groups, indicating little sedation at the relatively high dose used in this study. Not only does this careful study provide much needed additional information on the pharmacology of AZD7325 in native neurons, it also further demonstrates how the antiseizure properties of AEDs can be influenced by genetic background. Going forward, future work of this type will help develop more rational therapies for the treatment of these complex neurological disorders.