Biology subjects

Dickman, D.

Publications and source records attributed to Dickman, D..

5 recordsLinked to original sources

bioRxiv2018

The sleep gene insomniac ubiquitinates targets at postsynaptic densities and is required for retrograde homeostatic signaling

The nervous system confronts challenges during development and experience that can destabilize information processing. To adapt to these perturbations, synapses homeostatically adjust synaptic strength, a process referred to as homeostatic synaptic plasticity. At the Drosophila neuromuscular junction, inhibition of postsynaptic glutamate receptors activates retrograde signaling that precisely increases presynaptic neurotransmitter release to restore baseline synaptic strength. However, the nature of the underlying postsynaptic induction process remains enigmatic. Here, we designed a forward genetic screen to identify factors necessary in the postsynaptic compartment to generate retrograde homeostatic signaling. This approach identified insomniac (inc), a gene that encodes a putative adaptor for the Cullin-3 ubiquitin ligase complex and is essential for normal sleep regulation. Intriguingly, we find that Inc rapidly traffics to postsynaptic densities and is required for increased ubiquitination following acute receptor inhibition. Our study suggests that Inc-dependent ubiquitination, compartmentalized at postsynaptic densities, gates retrograde signaling and provides an intriguing molecular link between the control of sleep behavior and homeostatic plasticity at synapses.

neuroscience↗

bioRxiv2018

A screen for genes that regulate synaptic growth reveals mechanisms that stabilize synaptic strength

Synapses grow, prune, and remodel throughout development, experience, and disease. This structural plasticity can destabilize information transfer in the nervous system. However, neural activity remains remarkably stable throughout life, implying that adaptive countermeasures exist to stabilize neurotransmission. Aberrant synaptic structure and function has been associated with a variety of neural diseases including Fragile X syndrome, autism, and intellectual disability. We have screened disruptions in over 300 genes in Drosophila for defects in synaptic growth at the neuromuscular junction. This effort identified 12 mutants with severe reductions or enhancements in synaptic growth. Remarkably, electrophysiological recordings revealed synaptic strength in all but one of these mutants was unchanged compared to wild type. We utilized a combination of genetic, anatomical, and electrophysiological analyses to illuminate three mechanisms that stabilize synaptic strength in the face of alterations in synaptic growth. These include compensatory changes in 1) postsynaptic receptor abundance; 2) presynaptic morphology; and 3) active zone structure. Together, this analysis identifies new genes that regulate synaptic growth and the adaptive strategies that synapses employ to homeostatically stabilize synaptic strength in response.\n\nAUTHOR SUMMARYThroughout development, maturation, experience, and disease, synapses undergo dramatic changes in growth and remodeling. Although these processes are necessary for learning and memory, they pose major challenges to stable function in the nervous system. However, neurotransmission is typically constrained within narrow physiological ranges, implying the existence of homeostatic mechanisms that maintain stable functionality despite drastic alterations in synapse number. In this study we investigate the relationship between synaptic growth and function across a variety of mutations in neural and synaptic genes in the fruitfly Drosophila melanogaster. Using the neuromuscular junction as a model system, we reveal three adaptive mechanisms that stabilize synaptic strength when synapses are dramatically under- or over-grown. Together, these findings provide insights into the strategies employed at both pre- and post-synaptic compartments to ensure stable functionality while allowing considerable flexibility in overall synapse number.

neuroscience↗

bioRxiv2018

Neuronal thresholds and correlations in the peripheral vestibular system during rotation discrimination

Neuronal and behavioral thresholds were measured simultaneously as trained male macaques performed a yaw rotation discrimination task in darkness. When corrected to account for variations in neuronal direction preferences, neurons in the vestibular nuclei and semicircular canal afferents had discrimination thresholds that were only two-fold smaller than behavioral thresholds. There was no significant trial-by-trial correlation between neuronal activity and perceptual decisions, despite the presence of significant pair-wise noise correlations. The lack of choice-related activity during rotation discrimination contrasts with the robust correlations observed previously between brainstem neurons and choices during translation perception. These results suggest task-dependent differences in subcortical processing of vestibular signals, as well as how signals related to perceptual decisions may propagate back to early stages of sensory processing.\n\nSIGNIFICANCE STATEMENTThis is the first ever simultaneous recordings of neural and behavioral thresholds during rotation discrimination. Its importance lies on the fact that the vestibular system provides an excellent model to probe origins of perception because directional selectivity signals are similar at many levels of processing, from afferents to cortex. The findings of similar neuronal and behavioral discrimination thresholds, significant inter-neuronal correlations, but lack of correlations between behavior and neuronal activity of both afferents and central brainstem neurons are intriguing and suggest task-dependent organization of early sensory areas.

neuroscience↗

bioRxiv2017

Ribosome profiling reveals post-translational signaling mechanisms drive the retrograde enhancement of presynaptic efficacy

Presynaptic efficacy can be modulated by retrograde control mechanisms, but the nature of these complex signaling systems remain obscure. We have developed and optimized a tissue specific ribosome profiling approach in Drosophila. We first demonstrate the ability of this technology to define genome-wide translational regulations. We then leverage this technology to test the relative contributions of transcriptional, translational, and post-translational mechanisms in the postsynaptic muscle that orchestrate the retrograde control of presynaptic function. Surprisingly, we find no changes in transcription or translation are necessary to enable retrograde homeostatic signaling. Rather, post-translational mechanisms appear to ultimately gate instructive retrograde communication. Finally, we find that a global increase in translation induces adaptive responses in both transcription and translation of protein chaperones and degradation factors to promote cellular proteostasis. Together, this demonstrates the power of ribosome profiling to define transcriptional, translational, and post-translational mechanisms driving retrograde signaling during adaptive plasticity.\n\nAUTHOR SUMMARYRecent advances in next-generation sequencing approaches have revolutionized our understanding of transcriptional expression in diverse systems. However, transcriptional expression alone does not necessarily report gene translation, the process of ultimate importance in understanding cellular function. To circumvent this limitation, biochemical tagging of ribosomes and isolation of ribosomally-associated mRNA has been developed. However, this approach, called TRAP, has been shown to lack quantitative resolution compared to a superior technology, ribosome profiling, which quantifies the number of ribosomes associated with each mRNA. Ribosome profiling typically requires large quantities of starting material, limiting progress in developing tissue-specific approaches. Here, we have developed the first tissue specific ribosome profiling system in Drosophila to reveal genome-wide changes in translation. We first demonstrate successful ribosome profiling from a specific tissue, muscle, with superior resolution compared to TRAP. We then use transcriptional and ribosome profiling to define transcriptional and translational adaptions necessary for synaptic signaling at the neuromuscular junction. Finally, we utilize ribosome profiling to demonstrate adaptive changes in cellular translation following cellular stress to muscle tissue. Together, this now enables the power of Drosophila genetics to be leveraged with translational profiling in specific tissues.

neuroscience↗

bioRxiv2017

Extended Synaptotagmin Is A Presynaptic ER Ca2+ Sensor That Promotes Neurotransmission And Synaptic Growth In Drosophila

The endoplasmic reticulum (ER) is an extensive presynaptic organelle, exerting important influences at synapses by responding to Ca2+ and modulating transmission, growth, lipid metabolism, and membrane trafficking. Despite intriguing evidence for these crucial functions, how presynaptic ER influences synaptic physiology remains enigmatic. To gain insight into this question, we have generated and characterized mutations in the single Extended Synaptotagmin (Esyt) ortholog in Drosophila. Esyts are evolutionarily conserved ER proteins with Ca2+ sensing domains that have recently been shown to orchestrate membrane tethering and lipid exchange between the ER and plasma membrane. We first demonstrate that Esyt localizes to an extensive ER structure that invades presynaptic terminals at the neuromuscular junction. Next, we show that synaptic growth, structure, function, and plasticity are surprisingly unperturbed at synapses lacking Esyt expression. However, presynaptic overexpression of Esyt leads to enhanced synaptic growth, neurotransmission, and sustainment of the vesicle pool during intense levels of activity, suggesting that elevated Esyt at the ER promotes constitutive membrane trafficking or lipid exchange with the plasma membrane. Finally, we find that Esyt mutants fail to maintain basal neurotransmission and short term plasticity at elevated extracellular Ca2+, consistent with Esyt functioning as an ER Ca2+ sensor that modulates synaptic activity. Thus, we identify Esyt as a presynaptic ER Ca2+ sensor that can promote neurotransmission and synaptic growth, revealing the first in vivo neuronal functions of this conserved gene family.

neuroscience↗