Acute stress induces an aberrant increase of presynaptic release of glutamate and cellular activation in the hippocampus of BDNFVal/Met mice. Issue 10 (31st July 2022)

• Record Type: Journal Article
• Authors: Musazzi, Laura; Tornese, Paolo; Sala, Nathalie; Lee, Francis S.; Popoli, Maurizio; Ieraci, Alessandro
• Is Part Of: Journal of cellular physiology. Volume 237:Issue 10(2022)
• Page Start: 3834
• Page End: 3844
• Publication Date: 2022-07-31
• Subjects: acute stress -- BDNF Val66Met polymorphism -- gene expression -- glutamate release -- mood disorders -- synaptic mechanisms; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30833
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Stressful life events are considered major risk factors for the development of several psychiatric disorders, though people differentially cope with stress. The reasons for this are still largely unknown but could be accounted for by individual genetic variants, previous life events, or the kind of stressors. The human brain‐derived neurotrophic factor (BDNF) Val66Met variant, which was found to impair intracellular trafficking and activity‐dependent secretion of BDNF, has been associated with increased susceptibility to develop several neuropsychiatric disorders, although there is still some controversial evidence. On the other hand, acute stress has been consistently demonstrated to promote the release of glutamate in cortico‐limbic regions and altered glutamatergic transmission has been reported in psychiatric disorders. However, it is not known if the BDNF Val66Met single‐nucleotide polymorphism (SNP) affects the stress‐induced presynaptic glutamate release. In this study, we exposed adult male BDNF Val/Val and BDNF Val/Met knock‐in mice to 30 min of acute restraint stress. Plasma corticosterone levels, glutamate release, protein, and gene expression in the hippocampus were analyzed immediately after the end of the stress session. Acute restraint stress similarly increased plasma corticosterone levels and nuclear glucocorticoid receptor levels and phosphorylation in both BDNF Val/Val and BDNF Val/Met mice. However, acute restraint stress induced higher increases in hippocampal presynaptic release of glutamate, phosphorylation of cAMP‐response element binding protein (CREB), and levels of the immediate early gene c‐fos of BDNF Val/Met compared to BFNF Val/Val mice. Moreover, acute restraint stress selectively increased phosphorylation levels of synapsin I at Ser 9 and at Ser 603 in BDNF Val/Val and BDNF Val/Met mice, respectively. In conclusion, we report here that the BDNF Val66Met SNP knock‐in mice display an altered response to acute restraint stress in terms of hippocampal glutamate release, CREB phosphorylation, and neuronal activation, compared to wild‐type animals. Taken together, these results could partially explain the enhanced vulnerability to stressful events of Met carriers reported in both preclinical and clinical studies. Abstract : Heterozygous brain‐derived neurotrophic factor (BDNF) Val66Met knock‐in mice display a higher response to acute restraint stress in terms of glutamate release and c‐fos gene expression. This was paralleled by different and selective phosphorylation of synapsin I at Ser 9 and Ser 603 in BDNF Val/Val and BDNF Val/Met mice respectively.