para^DS.S1231R homozygous adults exhibit a fully penetrant heat-induced (40[o]C of temperature) seizure phenotype within 2min of exposure.

para^DS.S1231R mutant flies exhibit spontaneous and heat-induced seizures. These flies display increased heat sensitivity compared to para^GEFS+ mutant flies, consistent with the difference in disease severity in humans.

At room temperature, para^DS.S1231R flies exhibit abnormal behaviors that appear to mimic partial seizures, such as repetitive grooming that often results in broken wings in aged flies. Some para^DS.S1231R flies display repetitive jerks of one or more legs that can result in the flies flipping onto their backs. However, at the normal rearing temperature (22-24[o]C), the spontaneous seizure-like events occur at low frequency and are variable in nature and duration.

Immersion of two-day-old para^DS.S1231R flies in a 40[o]C water bath results in a rapid decline in coordinated walking movements, following by the flies falling onto their backs or sides. Within 20 seconds of immersion in the water bath, 100% of both male and female para^DS.S1231R mutants exhibit seizures and continue to do so throughout the 2 minute heating period. Upon removal from the water bath, the flies rapidly resume walking/climbing behaviour. Heterozygous para^DS.S1231R flies exhibit a delay in seizure onset and a lower probability of seizure, compared to homozygous mutants. The majority of heterozygotes (89%) exhibit seizure activity and a lower 'total seizure time' compared to homozygotes, indicating that para^DS.S1231R is semi-dominant. At the lower temperature of 38[o]C, homozygous para^DS.S1231R flies still exhibit rapid seizure onset and a high maximal seizure probability.

At 38[o]C, trans-heterozygous para^GEFS+/para^DS.S1231R mutants show a reduced rather than an intermediate seizure probability compared with either homozygotes.

para^DS.S1231R mutant local neurons (LNs) exhibit both constitutive and conditional reduction in sodium current activity. Evoked firing frequency is constitutively decreased in para^DS.S1231R LNs.

At 23[o]C, para^DS.S1231R mutants exhibit regular burst firing characterised by slow-wave depolarizations capped by a variable number of spikelets. These mutants have a significant reduction in the burst frequency in para^DS.S1231R compared with control LNs. As the temperature increases towards 35[o]C, the burst frequency in para^DS.S1231R LNs do not exhibit the increase in burst frequency at 27-31[o]C, as in wild-type.

para^DS.S1231R flies fed with 5-HTP exhibit a significant dose-dependent reduction in total seizing time. Total seizing time is significantly reduced compared with non 5-HTP flies. The seizure time of flies that are returned to normal food following 5-HTP exposure is indistinguishable from that of controls. Feeding with 5-HTP partially rescues the reduced local neuron burst firing frequency in para^DS.S1231R mutants.

The spontaneous burst frequency in para^DS.S1231R flies fed 5-HTP is significantly increased compared with untreated para^DS.S1231R at 23[o]C. As the temperature rises towards 35[o]C, the burst frequency in both 5-HTP treated and untreated para^DS.S1231R local neurons is stable up to 32[o]C, at which point the frequency in both groups begins to decline before complete cessation at 35[o]C. However, the burst firing frequency of local neurons in 5-HTP treated para^DS.S1231R flies is significantly increased compared with that in untreated para^DS.S1231R flies for most of the temperature range. There is no change in local neuron spikelet frequency, spikelet threshold, or burst duration in para^DS.S1231R flies fed 5-HTP, indicating that treatment has no effect on the intrinsic properties of the local neurons.

Overall, treatment with 5-HTP does not directly reverse the effects of the para^DS.S1231R mutation on sodium channels, but suppresses the seizure phenotype by modulating circuit activity.