BackgroundRhythmic behaviors, such as walking and breathing, involve the coordinated activity of central pattern generators in the CNS, sensory feedback from the PNS, to motoneuron output to muscles. Unraveling the intrinsic electrical properties of these cellular components is essential to understanding this coordinated activity. Here, we examine the significance of the transient A-type K+ current (IA), encoded by the highly conserved Shal/Kv4 gene, in neuronal firing patterns and repetitive behaviors. While IA is present in nearly all neurons across species, elimination of IA has been complicated in mammals because of multiple genes underlying IA, and/or electrical remodeling that occurs in response to affecting one gene.Methodology/Principal FindingsIn Drosophila, the single Shal/Kv4 gene encodes the predominant IA current in many neuronal cell bodies. Using a transgenically expressed dominant-negative subunit (DNKv4), we show that IA is completely eliminated from cell bodies, with no effect on other currents. Most notably, DNKv4 neurons display multiple defects during prolonged stimuli. DNKv4 neurons display shortened latency to firing, a lower threshold for repetitive firing, and a progressive decrement in AP amplitude to an adapted state. We record from identified motoneurons and show that Shal/Kv4 channels are similarly required for maintaining excitability during repetitive firing. We then examine larval crawling, and adult climbing and grooming, all behaviors that rely on repetitive firing. We show that all are defective in the absence of Shal/Kv4 function. Further, knock-out of Shal/Kv4 function specifically in motoneurons significantly affects the locomotion behaviors tested.Conclusions/SignificanceBased on our results, Shal/Kv4 channels regulate the initiation of firing, enable neurons to continuously fire throughout a prolonged stimulus, and also influence firing frequency. This study shows that Shal/Kv4 channels play a key role in repetitively firing neurons during prolonged input/output, and suggests that their function and regulation are important for rhythmic behaviors.

a-Enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid during glycolysis. It is a multifunctional oncoprotein that is present both in cell surface and cytoplasm, contributing to hit seven out of ten "hallmarks of cancer." ENO1's glycolytic function deregulates cellular energetic, sustains tumor proliferation, and inhibits cancer cell apoptosis. Moreover, ENO1 evades growth suppressors and helps tumors to avoid immune destruction. Besides, ENO1 "moonlights" on the cell surface and acts as a plasminogen receptor, promoting cancer invasion and metastasis by inducing angiogenesis. Overexpression of ENO1 on a myriad of cancer types together with its localization on the tumor surface makes it a great prognostic and diagnostic cancer biomarker as well as an accessible oncotherapeutic target. This review summarizes the up-todate knowledge about the relationship between ENO1 and cancer, examines ENO1's potential as a cancer biomarker, and discusses ENO1's role in novel onco-immunotherapeutic strategies. OVERVIEW OF ENO1 AND ITS ROLE IN CANCERENO1 is a multifunctional protein that partakes in various key intracellular and extracellular activities, depending on its localization (Figure 1). The primary function of ENO1 is to catalyze glycolysis; in

Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly. β-amyloid (Aβ) accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. Aβ has been shown to promote neuronal hyperactivity, which is consistent with enhanced seizure activity in mouse models and AD patients. Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of AD. Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. Interestingly, we find that loss of Kv4 alone results in learning and locomotion defects, as well as a shortened lifespan. To test whether the Aβ42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in Aβ42-expressing animals. We show that restoration of Kv4 attenuated age-dependent learning and locomotor deficits, slowed the onset of neurodegeneration, and partially rescued premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.

Long–term synaptic changes, which are essential for learning and memory, are dependent on homeostatic mechanisms that stabilize neural activity. Homeostatic responses have also been implicated in pathological conditions, including nicotine addiction. Although multiple homeostatic pathways have been described, little is known about how compensatory responses are tuned to prevent them from overshooting their optimal range of activity. We show that prolonged inhibition of nicotinic acetylcholine receptors (nAChRs), the major excitatory receptor in the Drosophila CNS, results in a homeostatic increase in the Dα7 nAChR. This response then induces an increase in the transient A–type K+ current carried by Shal/Kv4 channels. While increasing Dα7 boosts mEPSCs, the ensuing increase in Shal channels serves to stabilize postsynaptic potentials. This identifies a novel mechanism to fine–tune the homeostatic response.

In recent years, emerging studies have observed gut microbiota (GM) alterations in Alzheimer's disease (AD), even in individuals with mild cognitive impairment (MCI). Further, impaired sleep and circadian patterns are common symptoms of AD, while sleep and circadian rhythm disruption (SCRD) is associated with greater β-amyloid (Aβ) burden and AD risk, sometimes years before the clinical onset of AD. Moreover, reports have demonstrated that GM and its metabolites exhibit diurnal rhythmicity and the role of SCRD in dampening the GM rhythmicity and eubiosis. This review will provide an evaluation of clinical and animal studies describing GM alterations in distinct conditions, including AD, sleep and circadian disruption. It aims to identify the overlapping and distinctive GM alterations in these conditions and their contributions to pathophysiology. Although most studies are observational and use different methodologies, data indicate partial commonalities in GM alterations and unanimity at functional level. Finally, we discuss the possible interactions between SCRD and GM in AD pathogenesis, as well as several methodological improvements that are necessary for future research.