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Michael Gliksberg - Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 7610001, Israel

Ido Shirat - Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 7610001, Israel

Amrutha Swaminathan - Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 7610001, Israel

Gil Levkowitz - Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 7610001, Israel.  

Talia Levitas-Djerbi - The Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, 5290002, Israel.  

Lior Appelbaum - The Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, 5290002, Israel.  

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 resilient phenotype. Our study presents a unique genetic model demonstrating how early-life state of anxiety paradoxically correlates with reduced stress susceptibility in adulthood.

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Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior
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Michael Gliksberg - Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 7610001, Israel

Ido Shirat - Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 7610001, Israel

Amrutha Swaminathan - Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 7610001, Israel

Gil Levkowitz - Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 7610001, Israel.  

Talia Levitas-Djerbi - The Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, 5290002, Israel.  

Lior Appelbaum - The Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, 5290002, Israel.  

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

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 resilient phenotype. Our study presents a unique genetic model demonstrating how early-life state of anxiety paradoxically correlates with reduced stress susceptibility in adulthood.

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