RASGRF1 in CRF cells controls the early adolescent female response to repeated stress

in Journal of Endocrinology
Authors:
Shan-xue Jin Department of Developmental, Molecular, and Chemical Biology, Boston, Massachusetts, USA

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David A Dickson Department of Developmental, Molecular, and Chemical Biology, Boston, Massachusetts, USA
Neuroscence Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA

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Jamie Maguire Neuroscence Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA

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Larry A Feig Department of Developmental, Molecular, and Chemical Biology, Boston, Massachusetts, USA
Neuroscence Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA

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Correspondence should be addressed to L A Feig: larry.feig@tufts.edu

*(S Jin and D A Dickson contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-19-0375
Volume/Issue:
Volume 245: Issue 3
Article Type:
Research Article
Page Range:
397–410
Online Publication Date:
Jun 2020
Copyright:
© 2020 Society for Endocrinology 2020
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RASGRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates RAS and RAC GTPases. In hippocampus neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after 7 days of restraint stress (7DRS) (30 min/day) both elevated serum CORT levels and induction of an anxiolytic phenotype normally observed in early adolescent (EA) female mice are blocked in GRF1-knockout mice. In contrast, no effects were observed in EA male or adult females. Here, we show this phenotype is due, at least in part, to GRF1 loss in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockout specifically in these cells suppressed 7DRS-induced elevation of serum CORT levels specifically in EA females, but only down to levels found in comparably stressed EA males. Nevertheless, it still completely blocked the 7DRS-induced anxiolytic phenotype observed in EA females. Interestingly, loss of GRF1 in CRF cells had no effect after only three restraint stress exposures, implying a role for GRF1 in 7DRS stress-induced plasticity of CRF cells that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response EA females display to repeated stress.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
14
Article Type:
Research Article
Received Date:
24 Mar 2020
Accepted Date:
02 Apr 2020
Print Publication Date:
01 Jun 2020
Online Publication Date:
Jun 2020
Keywords:
HPA axis; RASGRF1; CRF cells; stress; adolescent females; neuron plasticity

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