Acute regulation of habituation learning via posttranslational palmitoylation

Nelson, Jessica C.; Witze, Eric S.; Ma, Zhongming; Ciocco, Francesca; Frerotte, Abigaile; Foskett, J. Kevin; Granato, Michael

doi:10.1101/570044

Cited by 4 publications

(12 citation statements)

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“…Cell culture studies have shown that Kv1.1 is highly glycosylated, and glycosylation is required for Kv1.1 channel function [49][50][51]. We confirmed the kinematic defect in the screen p181 allele ( Fig 3C-O) is due to the missense mutation in kcna1a using a previously generated kcna1a CRISPR allele (p410) [24]. p181/p410 transheterozygotes display the same exaggerated movements as mutants homozygous for p181…”

Section: The Glycosylation Pathway Protein Dolk Regulates Swim Magnitudesupporting

confidence: 75%

“…In this line, we identified a missense mutation in kcna1a, which encodes the voltage potassium Shaker-like channel subunit Kv1.1 (Fig 3A,B) [24]. Cell culture studies have shown that Kv1.1 is highly glycosylated, and glycosylation is required for Kv1.1 channel function [49][50][51].…”

Section: The Glycosylation Pathway Protein Dolk Regulates Swim Magnitudementioning

confidence: 95%

“…We previously performed a forward genetic screen for regulators of the acoustic startle response [23][24][25][26]. In brief, using a high-speed camera and automatic tracking, individual F3 larvae were exposed to a series of startling stimuli (for details on mutagenesis and the breeding scheme to obtain F3 larvae see [23]).…”

Section: A Forward Genetic Screen For Regulators Of the Larval Startlmentioning

confidence: 99%

“…To address whether dolk is critical for Kv1.1 localization or stability, we examined Kv1.1 protein localization in dolk mutants using a previously validated antibody [24]. In mammals, Kv1.1 is broadly expressed throughout the brain and primarily localizes to axons and axon terminals [53].…”

Section: Dolk Is Required For Axonal Localization Of Kv11mentioning

confidence: 99%

“…We previously performed a forward genetic approach to identify functional regulators of the acoustic startle response. This approach identified a distinct sets of genes with previously unrecognized roles critical for startle habituation [23,24], startle sensitivity [25], and sensorimotor decision making [26]. Here, we describe kinematic mutants identified from this screen that display defects in executing swim movements of the startle response.…”

Section: Introductionmentioning

confidence: 99%

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A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

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Nelson

Marsden

et al. 2020

Preprint

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The acoustic startle response is an evolutionary conserved avoidance behavior. Disruptions in startle behavior, in particular startle magnitude, are a hallmark of several human neurological disorders. While the neural circuitry underlying startle behavior has been studied extensively, the repertoire of genes and genetic pathways that regulate this locomotor behavior has not been explored using an unbiased genetic approach. To identify such genes, we took advantage of the stereotypic startle behavior in zebrafish larvae and performed a forward genetic screen coupled with whole genome analysis. This identified mutants in eight genes critical for startle behavior, including two genes encoding proteins associated with human neurological disorders, Dolichol kinase (Dolk), a broadly expressed regulator of the glycoprotein biosynthesis pathway, and the potassium Shaker-like channel subunit Kv1.1. We demonstrate that Kv1.1 acts independently of supraspinal inputs to regulate locomotion, suggesting its site of action is within spinal circuitry.Moreover, we show that Kv1.1 protein is mis-localized in dolk mutants, suggesting they act in a common genetic pathway to regulate movement magnitude. Combined, our results identify a diverse set of eight genes all associated with human disorders that regulate zebrafish startle behavior and reveal a previously unappreciated role for Dolk and Kv1.1 in regulating movement magnitude via a common genetic pathway. Author summaryUnderlying all animal behaviors are neural circuits, which are controlled by numerous molecular pathways that direct neuron development and activity. To identify and study these molecular pathways that control behavior, we use a simple vertebrate behavior, the acoustic startle response, in the larval zebrafish. In response to an intense noise, larval zebrafish will quickly turn 3 and swim away to escape. From a genetic screen, we have identified a number of mutants that behave in abnormal ways in response to an acoustic stimulus. We cloned these mutants and identified eight genes that regulate startle behavior. All eight genes are associated with human disorders, and here we focus on two genes, dolk and kcna1a, encoding Dolk, a key regulator of protein glycosylation, and the potassium channel Kv1.1, respectively. We demonstrate that loss of dolk or kcna1a causes larval zebrafish to perform exaggerated swim movements and that Dolk is required for Kv1.1 protein localization to axons of neurons throughout the nervous system, providing strong evidence that dolk and kcna1a act in a common molecular pathway. Combined, our studies provide new insights into the genetic regulation of startle behavior.

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Section: The Glycosylation Pathway Protein Dolk Regulates Swim Magnitudesupporting

confidence: 75%

Section: The Glycosylation Pathway Protein Dolk Regulates Swim Magnitudementioning

confidence: 95%

Section: A Forward Genetic Screen For Regulators Of the Larval Startlmentioning

confidence: 99%

Section: Dolk Is Required For Axonal Localization Of Kv11mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

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Nelson

Marsden

et al. 2020

Preprint

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A neuronal circuit that generates the temporal motor sequence for the defensive response in zebrafish larvae

Guan

Huang

et al. 2021

Current Biology

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Animals use a precisely timed motor sequence to escape predators. This requires the nervous system to coordinate several motor behaviors and execute them in a temporal and smooth manner. We here describe a neuronal circuit that faithfully generates a defensive motor sequence in zebrafish larvae. The temporally specific defensive motor sequence consists of an initial escape and a subsequent swim behavior and can be initiated by unilateral stimulation of a single Mauthner cell (M-cell). The smooth transition from escape behavior to swim behavior is achieved by activating a neuronal chain circuit, which permits an M-cell to drive descending neurons in bilateral nucleus of medial longitudinal fascicle (nMLF) via activation of an intermediate excitatory circuit formed by interconnected hindbrain cranial relay neurons. The sequential activation of M-cells and neurons in bilateral nMLF via activation of hindbrain cranial relay neurons ensures the smooth execution of escape and swim behaviors in a timely manner. We propose an existence of a serial model that executes a temporal motor sequence involving three different brain regions that initiates the escape behavior and triggers a subsequent swim. This model has general implications regarding the neural control of complex motor sequences.

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The Palmitoyl Acyltransferase ZDHHC14 Controls Kv1-Family Potassium Channel Clustering at the Axon Initial Segment

Sanders

Hernandez

Soh

et al. 2020

Preprint

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The palmitoyl acyltransferase (PAT) ZDHHC14 is highly expressed in the hippocampus and is the only PAT predicted to bind Type I PDZ domain-containing proteins. However, ZDHHC14’s neuronal roles are unknown. Here, we identify the PDZ domain-containing Membrane-associated Guanylate Kinase (MaGUK) PSD93 as a direct ZDHHC14 interactor and substrate. PSD93, but not other MaGUKs, localizes to the Axon Initial Segment (AIS). Using lentiviral-mediated shRNA knockdown in rat hippocampal neurons, we find that ZDHHC14 controls palmitoylation and AIS clustering of PSD93 and also of Kv1 potassium channels, which directly bind PSD93. Neurodevelopmental expression of ZDHHC14 mirrors that of PSD93 and Kv1 channels and, consistent with ZDHHC14’s importance for Kv1 channel clustering, loss of ZDHHC14 decreases outward currents and increases action potential firing in hippocampal neurons. To our knowledge, these findings identify the first neuronal roles and substrates for ZDHHC14 and reveal a previously unappreciated role for palmitoylation in control of neuronal excitability.Impact StatementZDHHC14 controls palmitoylation and axon initial segment targeting of PSD93 and Kv1-family potassium channels, events that are essential for normal neuronal excitability.

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Acute regulation of habituation learning via posttranslational palmitoylation

Cited by 4 publications

References 85 publications

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

A neuronal circuit that generates the temporal motor sequence for the defensive response in zebrafish larvae

The Palmitoyl Acyltransferase ZDHHC14 Controls Kv1-Family Potassium Channel Clustering at the Axon Initial Segment

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