The guanine nucleotide exchange factor, Spata13, influences social behaviour and nocturnal activity

Bourbia, Nora; Chandler, Paige; Codner, Gemma; Banks, Gareth; Nolan, Patrick M.

doi:10.1007/s00335-019-09800-9

Cited by 9 publications

(20 citation statements)

References 27 publications

(36 reference statements)

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“…Light/Dark box: Individual mice were placed into one corner of an enclosed arena separated into light and dark compartments (31). Over 20 minutes animal movements and position were monitored by EthoVision XT.…”

Section: Behavioural Phenotypingmentioning

confidence: 99%

“…Marble burying: Briefly, a cage was prepared with approximately 5cm deep sawdust bedding (31). 9 marbles were placed on the surface of the sawdust, evenly spaced in a regular pattern.…”

Section: Behavioural Phenotypingmentioning

confidence: 99%

“…Social dominance test: Dominant and submissive behaviours were assessed for pairs of male mice using a specialised Plexiglass tube (31). Pairs of mice, one wildtype and one homozygous mutant from different group-housed cages, were placed in the tube and behaviour registered as dominant ("win") or subordinate.…”

Section: Novel Object Recognitionmentioning

confidence: 99%

“…A forced alternation y-maze test was used to evaluate short term working memory in mice (31). Mice were video tracked at all times using Ethovision XT, preference for the novel arm is indicated by an occupancy of greater than 33%.…”

Section: Y-mazementioning

confidence: 99%

“…Mechanical sensitivity was assessed as in (34) Heat sensitivity, Hot Plate Test: A hot plate (BioSeb, Chaville, France) set at 51 o C was used for this test (31). Animals were placed on the plate and the latency to the first paw reflex (withdrawal reflex of one paw) was measured.…”

Section: Mechanical Sensitivity Von Frey Testmentioning

confidence: 99%

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Aberrant synaptic release underlies sleep/wake transition deficits in a mouseVamp2mutant

Banks

Guillaumin

Heise

et al. 2020

Preprint

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Sleep-wake transitions are modulated through extensive subcortical networks although the precise roles of their individual components remain elusive. Using forward genetics and in vivo electrophysiology, we identified a recessive mouse mutant line characterised by a reduced propensity to transition between all sleep states while a profound loss in total REM sleep time was evident. The causative mutation, an Ile102Asn substitution in VAMP2, was associated with substantial synaptic changes while in vitro electrophysiological investigations with fluorescence imaging revealed a diminished probability of vesicular release in mutants. We conclude that the synaptic efficiency of the entire subcortical brain network determines the likelihood that an animal transitions from one vigilance state to the next. Despite advances in our understanding of the neurophysiology of sleep (1, 2), the genetic regulation of its fundamental vigilance stateswakefulness, non-REM (NREM) sleep and REM sleepremains poorly understood. An extensive subcortical circuitry of neuromodulatory nuclei is thought to regulate global sleep-wake transitions, but the specific role of individual components remains to be determined. While high-throughput forward genetics screening has provided invaluable insights into the molecular genetic mechanisms underlying circadian rhythms (3-5), traditional electroencephalographic (EEG) methods of studying sleep are not conducive to highthroughput approaches and currently only a single study using such an approach has been published (6). Here, we adopted a high-throughput hierarchical approach, initially using behaviourally-defined sleep prior to EEG/EMG to identify mutant pedigrees with abnormal sleep-wake parameters in N-ethyl-N-nitrosourea (ENU) G3 pedigrees. Cloning and sequencing of the strongest phenodeviant pedigree identified a mis-sense mutation in the transmembrane domain of VAMP2, the core vSNARE protein mediating synaptic vesicle fusion and neurotransmitter release. EEG analysis confirmed the reduced sleep phenotype and revealed a marked decrease in REM sleep. Furthermore, while the EEG signatures of the different vigilance states were largely unaffected, VAMP2 mutant animals showed a profound deficit in their capacity to switch states once a specific state had been initiated. To determine how such a previously unexplored phenotype may arise we show, using cellular, molecular, imaging and electrophysiological studies, that vesicular release efficiency and shortterm plasticity are drastically affected in mutants. The consequences of this deficit in neuronal firing and the inherent inertia in state switching demonstrates a hitherto uncharacterised role for VAMP2 in sleep and highlights how new aspects of gene function, even for well-characterised genes, continue to be uncovered using forward genetics.

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Section: Behavioural Phenotypingmentioning

confidence: 99%

“…Marble burying: Briefly, a cage was prepared with approximately 5cm deep sawdust bedding (31). 9 marbles were placed on the surface of the sawdust, evenly spaced in a regular pattern.…”

Section: Behavioural Phenotypingmentioning

confidence: 99%

Section: Novel Object Recognitionmentioning

confidence: 99%

Section: Y-mazementioning

confidence: 99%

Section: Mechanical Sensitivity Von Frey Testmentioning

confidence: 99%

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