Chronic memantine disrupts spatial memory and up-regulates Htr1a gene expression in the hippocampus of GPR39 (zinc-sensing receptor) KO male mice.

Abstract

GPR39 is a receptor involved in zincergic neurotransmission, and its role in regulating psychological functions is an active area of research. The purported roles of GPR39 at the cellular level include regulation of inflammatory and oxidative stress response, and modulation of GABAergic and endocannabinoid neurotransmission. GPR39 knock-out (KO) mice exhibit episodic-like and spatial memory (ELM and SM, respectively) deficits throughout their lifetime, and are similar in that respect to senescent wild-type (WT) conspecifics. Since a role for zinc has been postulated in neurodegenerative disorders, in this study we investigated the possibility of a pharmacological rescue of both types of declarative memory with memantine - a noncompetitive NMDAR antagonist used for slowing down dementia; or, a putative GPR39 agonist - TC-G 1008. First, we tested adult WT and GPR39KO male mice under acute 5 mg/kg memantine or vehicle treatment in an object recognition task designed to simultaneously probe the "what?", "where?" and "when?" components of ELM. Next, we investigated the impact of chronic memantine or TC-G 1008 on ELM and SM (Morris water maze, MWM) in both WT and GPR39KO mice. Following chronic experiments, we assessed with qRT-PCR hippocampal gene expression of targets previously associated with GPR39. We report: no effects of acute memantine on ELM; a tendency to improve the "where?" component of ELM in both WT and GPR39 KO mice following 12 days of memantine; and, a disruption of SM in GPR39KO mice after 24 days of memantine treatment. The latter result was associated with upregulation of Htr1a hippocampal expression.

• Authors: Michal Rychlik, Joanna Starnowska-Sokol, Katarzyna Mlyniec
• Journal: Brain research (Brain Res) Vol. 1821 Pg. 148577 (12 15 2023) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 37716463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• GPR39 protein, mouse
• GPR39-C3
• Memantine
• Receptors, G-Protein-Coupled
• Zinc

Topics

• Animals
• Male
• Mice
• Gene Expression
• Hippocampus (metabolism)
• Memantine (pharmacology, metabolism)
• Mice, Knockout
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Spatial Memory
• Zinc (metabolism)