Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice

Abstract

BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders.Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors and is most highly concentrated in the hippocampus and frontal cortex (Baquet et al. 2004). BDNF has been implicated in a number of processes includ-

Potential translational targets revealed by linking mouse grooming behavioral phenotypes to gene expression using public databases

“…They also show altered anxiety phenotypes (Skelton et al, 2003), whereas its human ortholog PTPRA resides in the 20p13 region which has repeatedly been linked to psychosis (Fanous et al, 2008, Teltsh et al, 2008). As already suggested in the literature (Audet, Goulet, 2006, Isingrini et al, 2011, Papaleo et al, 2011), grooming responses in mice may represent traits highly relevant to schizophrenia, anxiety and depression, and our results are in line with this notion.…”

Growth factor signaling and memory formation: temporal and spatial integration of a molecular network

“…A global increase in BDNF could, in principle, cause more harm than good. Indeed, overexpression of BDNF has been reported to increase anxiety-like behavior, seizure activity, and impair some forms of memory (Croll et al 1999;Govindarajan et al 2006;Cunha et al 2009;Papaleo et al 2011). …”

Disruption of glucocorticoid receptors in the noradrenergic system leads to BDNF up-regulation and altered serotonergic transmission associated with a depressive-like phenotype in female GRDBHCre mice

“…14 Papaleo et al, 2011). From literature data it seem that BDNF and TrkB are important for antidepressant drug action however their role in development of depressive like symptoms remains uncertain (for review see Lindholm and Castren, 2014).…”

“…Moreover it has been shown that mice with forebrain overexpression of BDNF show gender differences in depressive-like behavior and can cause working memory impairments. Specifically males overexpressing BDNF has been shown to exhibit antidepressant-like effect in Porsolt Swim Test (Govindarajan et al, 2006) while females did not (Papaleo et al, 2011). Furthermore females overexpressing BDNF displayed impaired working memory and both sexes exhibited increased anxiety (Govindarajan et al, 2006, A C C E P T E D M A N U S C R I P T…”