Associative Learning Requires Neurofibromin to Modulate GABAergic Inputs to Drosophila Mushroom Bodies

Georganta, Eirini-Maria; Moressis, Anastasios; Skoulakis, Efthimios M. C.

doi:10.1523/jneurosci.1605-20.2021

Cited by 10 publications

(29 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings raise the possibility that sleep dysregulation is due to altered GABA signaling. Supporting this notion, GABA signaling to the mushroom bodies, the Drosophila memory center, is dysregulated in Nf1 mutants (Georganta et al, 2021). It has also previously been reported that Nf1 knockdown in GABA A receptor neurons leads to shortened sleep bouts and reduced sleep duration (Maurer et al, 2020).…”

Section: Discussionmentioning

confidence: 95%

“…Taken together, loss of Nf1 results in sleep fragmentation, reduced arousal threshold, and loss of sleepdependent changes in metabolic rate, suggesting that Nf1 is required for flies to enter deep sleep. While Nf1 is broadly expressed throughout the brain, its function has been linked to the modulation of GABA signaling during the formation of associative memories (Georganta et al, 2021). In Drosophila, the GABAA receptor Resistant to dieldrin (Rdl) is expressed in numerous populations of sleep-regulating neurons (Fig 4A; Chung et al, 2009;Driscoll et al, 2021;Parisky et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

“…While Nf1 is broadly expressed throughout the brain, its function has been linked to the modulation of GABA signaling during the formation of associative memories (Georganta et al, 2021). In Drosophila , the GABA A receptor Resistant to dieldrin (Rdl) is expressed in numerous populations of sleep-regulating neurons (Fig 4A; Chung et al, 2009; Driscoll et al, 2021; Parisky et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Neurofibromin 1 mediates sleep depth in Drosophila

Brown

Zhang

Lloyd

et al. 2022

Preprint

View full text Add to dashboard Cite

Neural regulation of sleep and metabolic homeostasis are critical in many aspects of human health. Despite extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic function. The RAS GTPase-activating gene Neurofibromin (Nf1) has been implicated in the regulation of sleep and metabolic rate, raising the possibility that it serves to integrate these processes, but the effects on sleep consolidation and physiology remain poorly understood. A key hallmark of sleep depth in mammals and flies is a reduction in metabolic rate during sleep. Here, we use indirect calorimetry to define the role of Nf1 on sleep-dependent changes in metabolic rate. Flies lacking Nf1 fail to suppress metabolic rate during sleep, raising the possibility that loss of Nf1 prevents flies from integrating sleep and metabolic state. Sleep of Nf1 mutant flies is fragmented with a reduced arousal threshold in Nf1 mutants, suggesting Nf1 flies fail to enter deep sleep. The effects of Nf1 on sleep can be localized to a subset of neurons expressing the GABA receptor Rdl. Selective knockdown of Nf1 in Rdl-expressing neurons increases gut permeability and reactive oxygen species (ROS) in the gut, suggesting a critical role for deep sleep in gut homeostasis. Together, these findings suggest Nf1 acts in GABA-sensitive neurons to modulate sleep depth in Drosophila.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Neurofibromin 1 mediates sleep depth in Drosophila

Brown

Zhang

Lloyd

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Mirroring Nf1- mutant mouse findings, dNf1 loss results in increased GABAergic signaling and disrupted associative learning. Importantly, learning is not restored following pharmacologic cAMP restoration, indicating that GABAergic signaling occurs independently of cAMP/PKA signaling in dNf1 -mutant flies ( Georganta et al, 2021 ). Together, these observations reveal RAS-cAMP-dependent long-term memory and RAS-cAMP-independent short-term memory functions of neurofibromin in Drosophila neurons.…”

Section: Neurofibromin and Non-canonical Ras Pathway Signalingmentioning

confidence: 99%

RAS and beyond: the many faces of the neurofibromatosis type 1 protein

Anastasaki

Orozco

Gutmann

2022

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the cloning of the NF1 gene and the recognition that the encoded protein, neurofibromin, largely functions as a negative regulator of RAS activity, attention has mainly focused on RAS and canonical RAS effector pathway signaling relevant to disease pathogenesis and treatment. However, as neurofibromin is a large cytoplasmic protein the RAS regulatory domain of which occupies only 10% of its entire coding sequence, both canonical and non-canonical RAS pathway modulation, as well as the existence of potential non-RAS functions, are becoming apparent. In this Special article, we discuss our current understanding of neurofibromin function.

show abstract

“…circuits (He et al, 2019;Liu et al, 2020), learning and memory circuits (Scaplen et al, 2020;Georganta et al, 2021), and circuits controlling aggression (Hu et al, 2020;Wu et al, 2020), social attraction (Sun et al, 2020), and circadian rhythm and sleep (Guo et al, 2018;Dreyer et al, 2019;Liu et al, 2019;Duhart et al, 2020). It has also been applied to identify neuropeptide synapses (Zandawala et al, 2018(Zandawala et al, , 2021 and other neuronal targets, such as the adipose tissue (Scopelliti et al, 2019).…”

Section: Applications Of Genetic Transsynaptic Toolsmentioning

confidence: 99%

Genetic Transsynaptic Techniques for Mapping Neural Circuits in Drosophila

2021

Front. Neural Circuits

View full text Add to dashboard Cite

A neural circuit is composed of a population of neurons that are interconnected by synapses and carry out a specific function when activated. It is the structural framework for all brain functions. Its impairments often cause diseases in the nervous system. To understand computations and functions in a brain circuit, it is of crucial importance to identify how neurons in this circuit are connected. Genetic transsynaptic techniques provide opportunities to efficiently answer this question. These techniques label synapses or across synapses to unbiasedly label synaptic partners. They allow for mapping neural circuits with high reproducibility and throughput, as well as provide genetic access to synaptically connected neurons that enables visualization and manipulation of these neurons simultaneously. This review focuses on three recently developed Drosophila genetic transsynaptic tools for detecting chemical synapses, highlights their advantages and potential pitfalls, and discusses the future development needs of these techniques.

show abstract

Associative Learning Requires Neurofibromin to Modulate GABAergic Inputs to Drosophila Mushroom Bodies

Cited by 10 publications

References 60 publications

Neurofibromin 1 mediates sleep depth in Drosophila

Neurofibromin 1 mediates sleep depth in Drosophila

RAS and beyond: the many faces of the neurofibromatosis type 1 protein

Genetic Transsynaptic Techniques for Mapping Neural Circuits in Drosophila

Contact Info

Product

Resources

About