Progesterone receptor expression in cajal‐retzius cells of the developing rat dentate gyrus: Potential role in hippocampus‐dependent memory

Abstract

The development of medial temporal lobe circuits is critical for subsequent learning and memory functions later in life. The present study reports the expression of progesterone receptor (PR), a powerful transcription factor of the nuclear steroid receptor superfamily, in Cajal-Retzius cells of the molecular layer of the dentate gyrus of rats. PR was transiently expressed from the day of birth through postnatal day 21, but was absent thereafter. Although PR immunoreactive (PR-ir) cells did not clearly express typical markers of mature neurons, they possessed an ultrastructural morphology consistent with neurons. PRir cells did not express markers for GABAergic neurons, neuronal precursor cells, nor radial glia. However, virtually all PR cells co-expressed the calcium binding protein, calretinin, and the glycoprotein, reelin, both reliable markers for Cajal-Retzius neurons, a transient population of developmentally critical pioneer neurons that guide synaptogenesis of perforant path afferents and histogenesis of the dentate gyrus. Indeed, inhibition of PR activity during the first two weeks of life impaired adult performance on both the novel object recognition and object placement memory tasks, two behavioral tasks hypothesized to describe facets of episodic-like memory in rodents. These findings suggest that PR plays an unexplored and important role in the development of hippocampal circuitry and adult memory function.

Glutamate released by Cajal-Retzius cells impacts specific hippocampal circuits and behaviors

“…For example, genetic depletion of CRs (with a parallel reduction in reelin levels at embryonic stages critical for hippocampal development) was shown to be associated with impaired learning and memory in adulthood ( Amelio et al, 2020 ). Furthermore, the systemic pharmacological inhibition of the progesterone receptor (which is transiently expressed by CRs; Newell et al, 2018 ) was reported to cause reelin accumulation in CRs and impaired episodic-like memory in mice ( Newell et al, 2021 ). However, neither of these studies measured the synaptic output of CRs and the less-selective manipulations used produced more complex outcomes.…”

Sex and age influence gonadal steroid hormone receptor distributions relative to estrogen receptor β‐containing neurons in the mouse hypothalamic paraventricular nucleus

“…Specificity of this antibody has been demonstrated by sucrose density gradients and absence of labeling in adsorption controls by immunoprecipitation methods, by preadsorption with the immunizing peptide (Haywood et al, 1999; Quadros et al, 2002; Quadros et al, 2007; Traish & Wotiz, 1990), and in thymus, uterus, and brain of PR knock‐out mice (Kurita et al, 1998; Tibbetts et al, 1999). In particular, nuclear immunoreactivity was completely abolished in all brain regions, including the hippocampus, following preadsorption of the PR peptide with either the antigen peptide (Genosys Biotechnologies, The Woodlands, TX) or a 10‐fold molar excess of human PR‐A and PR‐B proteins (Newell et al, 2018; Quadros et al, 2002). Additionally, immunoreactivity for this antiserum is eliminated in transgenic mice that possess an insertional mutation in the PR gene (i.e., PR knockout mice) (Newell et al, 2018).…”

“…In particular, nuclear immunoreactivity was completely abolished in all brain regions, including the hippocampus, following preadsorption of the PR peptide with either the antigen peptide (Genosys Biotechnologies, The Woodlands, TX) or a 10‐fold molar excess of human PR‐A and PR‐B proteins (Newell et al, 2018; Quadros et al, 2002). Additionally, immunoreactivity for this antiserum is eliminated in transgenic mice that possess an insertional mutation in the PR gene (i.e., PR knockout mice) (Newell et al, 2018). Following preadsorption, no immunolabeling for this antibody was observed at the EM level in acrolein/paraformaldyde hippocampal tissue (Waters et al, 2008).…”

“…Following preadsorption, no immunolabeling for this antibody was observed at the EM level in acrolein/paraformaldyde hippocampal tissue (Waters et al, 2008). This antibody has been used in prior studies for localizing PR immunoreactivity in mouse and rat hippocampus (Mitterling et al, 2010; Newell et al, 2018; Waters et al, 2008).…”

Adolescent stress during, but not after, pubertal onset impairs indices of prepulse inhibition in adult rats

“…Object recognition (OR) is a commonly used task to assess hippocampal-mediated recognition memory based on a rodent's natural tendency to explore unfamiliar objects. OR testing was conducted on P79 in two phases using the same protocol as Newell et al (2018). The first test was a habituation trial, where the animal was placed into the same testing apparatus used for OF and allowed to freely explore two identical objects for 5 min.…”