Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior.

Scientific Reports
Jakob BiranGil Levkowitz

Abstract

The pituitary adenylate cyclase-activating polypeptide receptor (PAC1, also known as ADCYAP1R1) is associated with post-traumatic stress disorder and modulation of stress response in general. Alternative splicing of PAC1 results in multiple gene products, which differ in their mode of signalling and tissue distribution. However, the roles of distinct splice variants in the regulation of stress behavior is poorly understood. Alternative splicing of a short exon, which is known as the "hop cassette", occurs during brain development and in response to stressful challenges. To examine the function of this variant, we generated a splice-specific zebrafish mutant lacking the hop cassette, which we designated 'hopless'. We show that hopless mutant larvae display increased anxiety-like behavior, including reduced dark exploration and impaired habituation to dark exposure. Conversely, adult hopless mutants displayed superior ability to rebound from an acute stressor, as they exhibited reduced anxiety-like responses to an ensuing novelty stress. We propose that the developmental loss of a specific PAC1 splice variant mimics prolonged mild stress exposure, which in the long term, predisposes the organism's stress response towards a resili...Continue Reading

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Citations

May 18, 2021·Neurobiology of Stress·Olga Y Ponomareva, Kerry J Ressler
Apr 26, 2021·Journal of Molecular Neuroscience : MN·Timea KvarikTamas Atlasz
Jan 4, 2022·Wiley Interdisciplinary Reviews. RNA·Marina Reixachs-Solé, Eduardo Eyras

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Methods Mentioned

BETA
antisense oligonucleotide
PCR
in vitro transcription
genotyping

Software Mentioned

EthoVision XT
Stream5
EthoVision
GraphPad Prism

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