Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice

Abstract

BackgroundSynaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown.ResultsIn this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the “immature DG” (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alpha-calcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants.ConclusionsThese findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders.

Chronic fluoxetine treatment reduces parvalbumin expression and perineuronal nets in gamma-aminobutyric acidergic interneurons of the frontal cortex in adult mice

“…Similar changes in DG neurons have been demonstrated in αCaMKII HKO [11], Shn-2 KO [18], and SNAP-25 KI mice [19]; this phenomenon has been termed the “immature DG” [10]. In this study, we demonstrate for the first time that FLX treatment might also induce dematuration of parvalbumin+ interneurons in the mFC and hippocampal CA3 region, while our finding in the amygdala is consistent with that of a previous study [20].…”

Transcriptomic immaturity of the hippocampus and prefrontal cortex in patients with alcoholism

“…To date, we have detected brain immaturity in various situations and hypothesized that the hyper-excitability of neurons is one of the causes of pseudo-immaturity in the hippocampus and PFC4; other reports also support an association between the hyper-excitation of neurons and neuronal dematuration910. In the present study, we detected immaturities in the brains of patients with alcoholism.…”

Genomic responses in mouse models greatly mimic human inflammatory diseases

“…Commentaries in response to the previous study claim that the implications of the study by Seok et al (1) may well go beyond mice and sepsis (10), and that better definitions of clinical phenotypes, especially in heterogeneous or overlapping conditions such as neurodevelopmental and psychiatric diseases, as well as more emphasis on rigorously defining molecular alterations in human patients, is needed (8). It should be noted that, even for schizophrenia, which could be considered a uniquely human disorder (17), recent mouse models have been developed using an approach similar to those used in the present study that are shown to closely recapitulate not only the clinical or behavioral phenotypes but also the molecular alterations in transcriptional and protein changes in the brain (18)(19)(20)(21).…”