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Traumatic brain injury (TBI) is a complex disorder that affects millions of people worldwide. The complexity of TBI partly stems from the fact that injuries to the brain instigate non-neurological injuries to other organs such as the intestine. Additionally, genetic variation is thought to play a large role in determining the nature and severity of non-neurological injuries. We recently reported that TBI in flies, as in humans, increases permeability of the intestinal epithelial barrier resulting in hyperglycemia and a higher risk of death. Furthermore, we demonstrated that genetic variation in flies is also pertinent to the complexity of non-neurological injuries following TBI. The goals of this review are to place our findings in the context of what is known about TBI-induced intestinal permeability from studies of TBI patients and rodent TBI models and to draw attention to how studies of the fly TBI model can provide unique insights that may facilitate diagnosis and treatment of TBI.

Recent evidence indicates that protein aggregates can spread between neurons in several neurodegenerative diseases but much remains unknown regarding the underlying mechanisms responsible for this spreading and its role in disease progression. We recently demonstrated that mutant Huntingtin aggregates spread between cells within the Drosophila brain resulting in non-cell autonomous loss of a pair of large neurons in the posterior protocerebrum. However, the full extent of neuronal loss throughout the brain was not determined. Here we examine the effects of driving expression of mutant Huntingtin in Olfactory Receptor Neurons (ORNs) by using a marker for cleaved caspase activity to monitor neuronal apoptosis as a function of age. We find widespread caspase activity in various brain regions over time, demonstrating that non-cell autonomous damage is widespread. Improved understanding of which neurons are most vulnerable and why should be useful in developing treatment strategies for neurodegenerative diseases that involve transcellular spreading of aggregates.

Neuropeptides are ubiquitous in both mammals and invertebrates and play essential roles in regulation and modulation of many developmental and physiological processes through activation of G-protein-coupled-receptors (GPCRs). However, the mechanisms by which many of the neuropeptides regulate specific neural function and behaviors remain undefined. Here we investigate the functions of Drosulfakinin (DSK), the Drosophila homolog of vertebrate neuropeptide cholecystokinin (CCK), which is the most abundant neuropeptide in the central nervous system. We provide biochemical evidence that sulfated DSK-1 and DSK-2 activate the CCKLR-17D1 receptor in a cell culture assay. We further examine the role of DSK and CCKLR-17D1 in the regulation of larval locomotion, both in a semi-intact larval preparation and in intact larvae under intense light exposure. Our results suggest that DSK/CCKLR-17D1 signaling promote larval body wall muscle contraction and is necessary for mediating locomotor behavior in stress-induced escape response.

Wallerian degeneration of axons occurs after axons have been injured or severed. In mice, a single protein, Wlds, has been shown to protect injured axons from degeneration for days, in contrast wit...

On the basis of behavioral interactions with mutations in a potassium channel gene of Drosophila--Shaker (Sh)--we have isolated mutations in a new gene called inebriated (ine). In a wildtype background, ine mutants display no observable behavioral defects. However, in a Sh mutant background, ine mutations cause downturned wings and an indented thorax. This distinctive phenotype is also exhibited by flies of other genotypes that cause extreme neuronal hyperexcitability. We utilized the potassium channel blocking drugs quinidine and dideoxy forskolin (DDF) to test the effects of ine on synaptic transmission. DDF and ine mutations each potentiated the effects of quinidine on synaptic transmission, but neither had any observable effects in the absence of quinidine. Application of DDF to ine mutants had no effects either in the presence or absence of quinidine. We conclude that ine mutations increase neuronal membrane excitability and perhaps block a DDF-sensitive potassium channel.

To study electrogenic conduction in neurons of the cervical giant nerve fiber (CGF) pathway in Drosophila adults carrying temperature-sensitive paralytic mutations that affect sodium channels, we recorded dorsal longitudinal muscle (DLM) responses evoked by electrical stimulation of the brain. In the mutants tipE, napts and parats, conduction in certain neurons presynaptic to the CGF failed at about the same temperature at which paralysis occurred in each mutant. Conduction in the CGF and neurons postsynaptic to it remained active in all mutants even at very elevated temperatures. In contrast, analysis of sei mutants showed enhanced spontaneous activity at elevated temperatures in at least some neurons of the CGF pathway. The implications of these results with respect to the normal in vivo functions of these genes in neuronal signalling are considered.

Recombinational dissection of the ShrK0120 strain of Drosophila melanogaster demonstrated that its extremely prolonged neuromuscular transmission, a defect qualitatively different from other Sh alleles, results from a synergistic interaction with a second site mutation. This new mutation caused spontaneous repetitive firing in motor axons and increased transmitter release. Complementation tests showed that it is allelic to eag. Combining either eag allele with various Sh alleles reproduced the same extreme defect observed in the original ShrK0120 strain. Thus, from their effects on neuromuscular transmission no qualitative difference among Sh alleles is apparent while Sh, eag, and eag Sh double mutant individuals can be uniquely distinguished. Pharmacological experiments indicated that Sh affects a membrane component sensitive to the potassium channel blockers 4-AP and TEA while eag affects a component sensitive to TEA but not 4-AP. We suggest that eag and Sh preferentially disrupt different potassium currents explaining their synergistic interaction.