The Neurogenesis Actuator and NR2B/NMDA Receptor Antagonist Ro25-6981 Consistently Improves Spatial Memory Retraining Via Brain Region-Specific Gene Expression

Abstract

NR2B-containing NMDA (NR2B/NMDA) receptors are important in controlling neurogenesis and are involved in generating spatial memory. Ro25-6981 is a selective antagonist at these receptors and actuates neurogenesis and spatial memory. Inter-structural neuroanatomical profiles of gene expression regulating adult neurogenesis and neuroapoptosis require examination in the context of memory retrieval and reversal learning. The aim was to investigate spatial memory retrieval and reversal learning in relation to gene expression-linked neurogenetic processes following blockade of NR2B/NMDA receptors by Ro25-6981. Rats were trained in Morris water maze (MWM) platform location for 5 days. Ro25-6981 was administered (protocol days 6–7) followed by retraining (days 15–18 or 29–32). Platform location was tested (on days 19 or 33) then post-mortem brain tissue sampling (on days 20 or 34). The expression of three genes known to regulate cell proliferation (S100a6), differentiation (Ascl1), and apoptosis (Casp-3) were concomitantly evaluated in the hippocampus, prefrontal cortex, and cerebellum in relation to the MWM performance protocol. Following initial training, Ro25-6981 enhanced visuospatial memory retrieval performance during further retraining (protocol days 29–32) but did not influence visuospatial reversal learning (day 33). Hippocampal Ascl1 and Casp-3 expressions were correspondingly increased and decreased while cerebellar S100a6 and Casp-3 activities were decreased and increased respectively 27 days after Ro25-6981 treatment. Chronological analysis indicated a possible involvement of new mature neurons in the reconfiguration of memory processes. This was attended by behavioral/gene correlations which revealed direct links between spatial memory retrieval enhancement and modified gene activity induced by NR2B/NMDA receptor blockade and upregulation.

Intrahippocampal injection of a selective blocker of NMDA receptors containing the GluN2B subunit, Ro25‐6981, increases glutamate neurotransmission and induces antidepressant‐like effects

“…Adult-born GCs bearing the GluN2B subunit of NMDA receptors exhibit unique properties by influencing behavioral responses to antidepressant drugs [21]. The systemic administration of Ro25-6981 also exhibits a fast antidepressant response (24,48, or 72 h later) in the a neurogenesis-dependent task, the Novelty Suppressed Feeding [22], but also in neurogenesisindependent behavioral assays, such as the forced swim test (FST) and the sucrose preference test (ST) ( [23] for review; [24][25][26]). Therefore, adult hippocampal neurogenesis does not seem to be necessary for Ro25-6981 antidepressant-like activity.…”

Loss of NMDA receptor function during development results in decreased KCC2 expression and increased neurons in the zebrafish forebrain

“…The specific role of NMDA receptors in regulating direct and indirect neurogenesis is unclear. Further highlighting the complex role of NMDA receptors in neurogenesis is that they have been proposed to both suppress [23][24][25][26] and promote [27][28][29][30][31] neurogenesis. These differences are presumably due to variations in specific NSPC focus and stages of neurogenesis investigated, each of which differentially contribute to direct and indirect neurogenesis.…”