Drosophila melanogaster in the study of epilepsy

NARA I. MURARO AND RICHARD A. BAINES

Drosophila: A toolbox for the study of Neurodegenerative disease

Taylor and Francis

Lugar: New York; Año: 2008; p. 141 - 160

Epilepsy is a widespread disorder that affects approximately 1% of the population (McNamara, 1994). A hallmark of epilepsy is the presence of recurrent spontaneous seizures, which arise from either the hyperexcitation and/or abnormal synchronization of neuronal circuit activity. Because the initial focus of aberrant excitation varies in different individuals, the known seizure phenotypes are diverse. Seizures often manifest as either general or partial involuntary skeletal muscle contractions associated with or without loss of consciousness. The most severe of seizures are the tonic-clonic which are associated with full paralysis and loss of consciousness followed by bouts of muscle activity prior to recovery. In absence epilepsy, seizures are characterized by a sudden and temporary discontinuation of an action in progress. More subtle seizures can consist of a transient distortion of the senses (psychomotor epilepsy). The first onset of seizure is most common in both the young and old indicative of the cause being associated with abnormal brain development and/or function. Therefore, unlike many diseases, epilepsy is a heterogeneous disorder that varies in seizure phenotype, age of onset and prognosis. Although epilepsy can develop secondary to brain injury or be caused by overt brain malformations, most epileptics do not present with abnormal brain structure. These idiopathic epilepsies almost certainly have a genetic basis although their heritability has proven to be complex. In spite of this, several genes have been associated with epilepsy (Steinlein, 2004). The majority of genes identified thus far encode ion channels or their accessory subunits, which places most epilepsies in a group of disorders termed channelopathies (Waxman, 2001). The identified ion channels belong to both the voltage-gated and ligand-gated types. For example, mutations in the voltage-gated sodium channels SCN1A, SCN2A and SCN1B have been associated to both a benign form of epilepsy, epilepsy with febrile seizures plus (GEFS+), and to severe myoclonic epilepsy of infancy (SMEI) (Mulley et al., 2005). This exemplifies further the complexity of epilepsy, where different mutations in the same gene can give rise to diverse clinical manifestations, and mutations in different genes can produce a similar phenotype. Mutations in the voltage-gated potassium channels KCNQ2 and KCNQ3 produce benign familiar neonatal convulsions (BFNC) (Cooper, 2001) and there are mutations in voltage-gated calcium channels that have been linked to absence epilepsy (Jones, 2002). Among the ligand-gated ion channels, mutations in a GABAA (g-aminobutyric acid, subunit A) receptor, as well as in nicotinic acetylcholine receptors have been linked to GEFS+ and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) respectively. A number of mutations in non-ion channels have also been associated to epilepsy, including respiratory chain proteins and cysteine protease inhibiters (Steinlein, 2004). Given the importance of ion channels for the generation and regulation of neuronal excitability, their implied role in epilepsy is unsurprising. Indeed, most anti-epileptic drugs (AED) described to date work by altering ion channel physiology (Rho and Sankar, 1999). However, although these AEDs are effective in controlling seizures in the majority, they do not prevent the occurrence of seizures and as such do not treat the disease itself. Since there is no cure known for epilepsy, and AEDs are ineffective in a significant minority (~30% of epileptics), the development of novel treatments is desirable. In order to provide novel treatments it is first implicit that the underlying causes of epilepsy are better understood.