Remote spatial memory deficits in mouse models of neuropsychiatric disorders with immature dentate gyrus phenotype

The hippocampal dentate gyrus (DG) is a critical region that contributes to recent and remote memory. Granule cells within this region, in which adult neurogenesis occurs, undergo dynamic and reversible maturation via genetic and environmental factors during adulthood. A pseudo-immature state of DG granule cells, called immature DG (iDG), has been observed in the adult mice of certain mutant strains, which are considered animal models of neuropsychiatric and neurodegenerative disorders, such as intellectual disability, schizophrenia, autism, and Alzheimer's disease. However, the association between the iDG phenotype and recent and remote memories in the mouse models remains unclear.

We assessed spatial memory in the Barnes circular maze task in five mutant mouse models of the disorders with the iDG phenotype, including Camk2a heterozygous knockout (HET KO), forebrain-specific Calcineurin (Cn) conditional KO (cKO), Neurogranin (Nrgn) KO, and Hivep2 (Schnurri-2) KO, and hAPP-J20 transgenic mice.

Camk2a HET KO mice and J20 mice spent less time around the target than their wild-type control mice in the memory retention tests 1 day and 4 weeks after the last training session. Cn cKO, Nrgn KO, and Schnurri-2 KO mice showed no significant differences in the time spent around the target from wild-type mice in the retention test 1 day after the training session, but those mutants spent less time around the target than their wild-type mice in the retest conducted 4 weeks later.

These results indicated that mouse models of neuropsychiatric and neurodegenerative disorders exhibiting the iDG phenotype demonstrate a common behavioral characteristic of remote spatial memory deficits, suggesting the potential involvement of the pseudo-immature state of DG granule cells in remote memory dysfunction. Significance Statement A pseudo-immature state of granule cells in the hippocampal dentate gyrus (DG), called immature DG (iDG), has been observed in several mutant strains of mice considered as animal models of neuropsychiatric and neurodegenerative disorders. Thus, the iDG phenotype is proposed as one of the characteristic features of some types of the disorders. However, the impacts of iDG phenotype on hippocampal functions remains unclear. This study demonstrated that two of the five genetically modified mouse strains with iDG phenotype exhibited deficits in both recent and remote memory, with the impairments being more pronounced at the remote delay. The other three strains showed selective deficits in remote memory. These observations suggest that the pseudo-immature state of DG is associated with remote memory dysfunction, although further studies are needed to determine the causality and elucidate the underlying mechanisms.