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Patients who have sustained a traumatic brain injury (TBI) exhibit clinical symptoms of widely varying types and severities. In contrast, because of cost, experimental flexibility, and animal welfare, preclinical rodent models of TBI are designed to exhibit relatively homogeneous symptoms. This disconnect may explain why drugs developed using rodent models have universally failed in clinical studies. We suggest that drug development for TBI could benefit from preclinical studies using non-mammalian animals, where cost, experimental flexibility, and animal welfare are less of an issue and variables that affect clinical symptoms, including genotype, age, and environmental factors, can be more extensively investigated.

Most of us sleep 7-8 h per night, and if we are deprived of sleep our performance suffers greatly; however, a few do well with just 3-4 h of sleep-a trait that seems to run in families. Determining which genes underlie this phenotype could shed light on the mechanisms and functions of sleep. To do so, we performed mutagenesis in Drosophila melanogaster, because flies also sleep for many hours and, when sleep deprived, show sleep rebound and performance impairments. By screening 9,000 mutant lines, we found minisleep (mns), a line that sleeps for one-third of the wild-type amount. We show that mns flies perform normally in a number of tasks, have preserved sleep homeostasis, but are not impaired by sleep deprivation. We then show that mns flies carry a point mutation in a conserved domain of the Shaker gene. Moreover, after crossing out genetic modifiers accumulated over many generations, other Shaker alleles also become short sleepers and fail to complement the mns phenotype. Finally, we show that short-sleeping Shaker flies have a reduced lifespan. Shaker, which encodes a voltage-dependent potassium channel controlling membrane repolarization and transmitter release, may thus regulate sleep need or efficiency.

Communication within the nervous system is mediated by Ca2+-triggered fusion of synaptic vesicles with the presynaptic plasma membrane. Genetic and biochemical evidence indicates that synaptotagmin I may function as a Ca2+ sensor in neuronal exocytosis because it can bind Ca2+ and penetrate into lipid bilayers1,2,3,4. Chronic depolarization or seizure activity results in the upregulation of a distinct and unusual isoform of the synaptotagmin family, synaptotagmin IV (ref. 5). We have identified a Drosophila homologue of synaptotagmin IV that is enriched on synaptic vesicles and contains an evolutionarily conserved substitution of aspartate to serine that abolishes its ability to bind membranes in response to Ca2+ influx. Synaptotagmin IV forms hetero-oligomers with synaptotagmin I, resulting in synaptotagmin clusters that cannot effectively penetrate lipid bilayers and are less efficient at coupling Ca2+ to secretion in vivo : upregulation of synaptotagmin IV, but not synaptotagmin I, decreases evoked neurotransmission. These findings indicate that modulating theexpression of synaptotagmins with different Ca2+-binding affinities can lead to heteromultimers that can regulate the efficiency of excitation–secretion coupling in vivo and represent a new molecular mechanism for synaptic plasticity.

We investigate the molecular and cellular etiologies that underlie the deletion of the six amino acid residues (DeltaF323-Y328; DeltaFY) in human torsin A (HtorA). The most common and severe mutation involved with early-onset torsion dystonia is a glutamic acid deletion (DeltaE 302/303; DeltaE) in HtorA which induces protein aggregates in neurons and cells. Even though DeltaFY HtorA forms no protein clusters, flies expressing DeltaFY HtorA in neurons or muscles manifested a similar but delayed onset of adult locomotor disability compared with flies expressing DeltaE in HtorA. In addition, flies expressing DeltaFY HtorA had fewer aberrant ultrastructures at synapses compared with flies expressing DeltaE HtorA. Taken together, the DeltaFY mutation in HtorA may be responsible for behavioral and anatomical aberrations in gDrosophila.

Single mutations that disrupt basic physiological processes such as axonal conduction and synaptic transmission provide one means to study the membrane components and mechanisms that underlie these processes1,8. Temperature-sensitive paralytic mutants of Drosophila melanogaster which behave normally at a permissive temperature (23–25 °C) but become paralysed at a restrictive temperature (usually 29–37 °C) have been utilized in such studies. An example is napts (no action potential, temperature-sensitive), a recessive second-chromosome mutation that causes paralysis of larvae and adults at 37 °C. Electrophysiological recordings have demonstrated that napts specifically affects a component of axonal membranes5. Here we show that axonal conduction in napts larvae is abnormally sensitive to tetrodotoxin (TTX), a specific blocker of voltage-sensitive sodium channels9, and that the refractory period of action potentials differs from wild type, consistent with the idea that napts alters the function of sodium channels. It is further shown that parats (paralysed, temperature-sensitive), a recessive X-linked mutation1, also specifically disrupts axonal conduction and that the two mutations affect functionally related membrane components. Identification of other mutants defective in associated components of nerve membranes is made feasible by using techniques described here.