Acute deletion of the central MR/GR steroid receptor correlates with changes in LTP, auditory neural gain, and GC-A cGMP signaling

Dila Calis; Morgan Hess; Philine Marchetta; Wibke Singer; Julian Modro; Ellis Nelissen; Jos Prickaerts; Peter Sandner; Robert Lukowski; Peter Ruth; Marlies Knipper; Lukas Rüttiger

doi:10.3389/fnmol.2023.1017761

Acute deletion of the central MR/GR steroid receptor correlates with changes in LTP, auditory neural gain, and GC-A cGMP signaling

Front Mol Neurosci. 2023 Feb 17:16:1017761. doi: 10.3389/fnmol.2023.1017761. eCollection 2023.

Authors

Affiliations

¹ Department of Otolaryngology, Head and Neck Surgery, Tübingen Hearing Research Centre, Molecular Physiology of Hearing, University of Tübingen, Tübingen, Germany.
² Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, Netherlands.
³ Bayer Health Care Pharmaceuticals, Global Drug Discovery Pharma Research Centre Wuppertal, Wuppertal, Germany.
⁴ Institute of Pharmacy, Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Tübingen, Germany.

Abstract

The complex mechanism by which stress can affect sensory processes such as hearing is still poorly understood. In a previous study, the mineralocorticoid (MR) and/or glucocorticoid receptor (GR) were deleted in frontal brain regions but not cochlear regions using a CaMKIIα-based tamoxifen-inducible Cre ^ERT2/loxP approach. These mice exhibit either a diminished (MR^TMXcKO) or disinhibited (GR^TMXcKO) auditory nerve activity. In the present study, we observed that mice differentially were (MR^TMXcKO) or were not (GR^TMXcKO) able to compensate for altered auditory nerve activity in the central auditory pathway. As previous findings demonstrated a link between central auditory compensation and memory-dependent adaptation processes, we analyzed hippocampal paired-pulse facilitation (PPF) and long-term potentiation (LTP). To determine which molecular mechanisms may impact differences in synaptic plasticity, we analyzed Arc/Arg3.1, known to control AMPA receptor trafficking, as well as regulators of tissue perfusion and energy consumption (NO-GC and GC-A). We observed that the changes in PPF of MR^TMXcKOs mirrored the changes in their auditory nerve activity, whereas changes in the LTP of MR^TMXcKOs and GR^TMXcKOs mirrored instead the changes in their central compensation capacity. Enhanced GR expression levels in MR^TMXcKOs suggest that MRs typically suppress GR expression. We observed that hippocampal LTP, GC-A mRNA expression levels, and ABR wave IV/I ratio were all enhanced in animals with elevated GR (MR^TMXcKOs) but were all lower or not mobilized in animals with impaired GR expression levels (GR^TMXcKOs and MRGR^TMXcKOs). This suggests that GC-A may link LTP and auditory neural gain through GR-dependent processes. In addition, enhanced NO-GC expression levels in MR, GR, and MRGR^TMXcKOs suggest that both receptors suppress NO-GC; on the other hand, elevated Arc/Arg3.1 levels in MR^TMXcKOs and MRGR^TMXcKOs but not GR^TMXcKOs suggest that MR suppresses Arc/Arg3.1 expression levels. Conclusively, MR through GR inhibition may define the threshold for hemodynamic responses for LTP and auditory neural gain associated with GC-A.

Keywords: GC-A; NO-GC; cognition; glucocorticoid receptor; mineralocorticoid receptor.