Inhibition of progesterone receptor activity during development increases reelin-immunoreactivity in Cajal-Retzius cells, alters synaptic innervation in neonatal dentate gyrus, and impairs episodic-like memory in adulthood

Abstract

Progesterone receptor (PR) is expressed in Cajal-Retzius (CR) cells of the dentate gyrus (DG) molecular layer during the postnatal period (P1–28), a critical stage of development for the dentate gyrus and its circuitry. CR cells secrete the glycoprotein, reelin, which is required for typical development of the DG and its connections, particularly afferent input from the perforant path. This pathway regulates the processing of sensory information arriving from entorhinal cortex and integrates this information to form episodic memories. To assess the potential role of PR activity on the development of these connections and associated behavior, rats were treated daily from P1 to 7 with the PR antagonist, RU486. RU486 treatment increased the number of reelin-ir cells, suggesting an accumulation of reelin, and implicating PR in the regulation of a principle developmental function of CR cells. RU486 also altered the synaptic bouton marker, synaptophysin-ir, in a sex-specific manner, suggesting a role for PR activity in the development of perforant path innervation of the molecular layer (MOL). Finally, both control and RU486 treated rats spent significantly more time with a temporally distant object in the Relative Recency task, suggesting an intact associative memory for object identity and temporal order in both groups. In contrast, the same RU486 treated rats were impaired in an episodic-like memory task compared to controls, failing to integrate object identity (‘what’), time (‘when’), and object position (‘where’). These findings reveal a novel role for PR in regulating CR cell function within the MOL, thereby altering development of DG connectivity and behavioral function.