Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

Abstract

Brain-derived neurotrophic factor (BDNF) is known to play a critical role in the synaptic plasticity underlying the acquisition and/or consolidation of certain forms of memory. Additionally, a role has been suggested for neurotrophin function within the hippocampus in protection from anxiety and depressive disorders. Understanding the function of this important gene in adult animals has been limited however, because standard knockouts are confounded by gene effects during development. There are no BDNF receptor-specific pharmacological agents, and infusions of neuropeptides or antibodies have other significant limitations. In these studies, we injected a lentivirus expressing Cre recombinase bilaterally into the dorsal hippocampus in adult mice floxed at the BDNF locus to facilitate the sitespecific deletion of the BDNF gene in adult animals. Significant decreases in BDNF mRNA expression are demonstrated in the hippocampi of lenti-Cre-infected animals compared with control lenti-GFP-infected animals. Behaviorally, there were no significant effects of BDNF deletion on locomotion or baseline anxiety measured with startle. In contrast, hippocampalspecific BDNF deletions impair novel object recognition and spatial learning as demonstrated with the Morris water maze. Although there were no effects on the acquisition or expression fear, animals with BDNF deletions show significantly reduced extinction of conditioned fear as measured both with fear-potentiated startle and freezing. These data suggest that the cognitive deficits and impairment in extinction of aversive memory found in depression and anxiety disorders may be directly related to decreased hippocampal BDNF.

Intrahippocampal Transplantation of Transgenic Neural Precursor Cells Overexpressing Interleukin-1 Receptor Antagonist Blocks Chronic Isolation-Induced Impairment in Memory and Neurogenesis

“…This finding does not corroborate previous research, which demonstrated that BDNF is an important modulator of hippocampal-dependent memory formation (Heldt et al, 2007) and neurogenesis (Lee et al, 2002), and that acute isolation stress produces an IL-1-mediated decrease in hippocampal BDNF expression and memory functioning (Barrientos et al, 2003). This discrepancy could stem from a procedural difference, because in contrast to all of the above-mentioned studies, in which BDNF levels were measured shortly after behavioral testing, in the present experiments the animals were killed 72 h after the end of the behavioral testing.…”

“…Isolated mice exhibited a significant 45% reduction in neurogenesis, as compared to group-housed mice (t 8 ¼ 10.73, po0.001) (Figure 1g). Because previous studies demonstrated that acute social isolation, as well as IL-1 administration, reduces the production of BDNF (Barrientos et al, 2003;Scaccianoce et al, 2006), which is involved in both memory processes and neurogenesis (Lee et al, 2002;Heldt et al, 2007), we also measured BDNF levels within the hippocampus. However, hippocampal BDNF levels were similar in isolated and group-housed mice (1548±134 and 1349±102 pg/ml, respectively) (p40.1).…”

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

“…Impaired fear extinction has been linked to increased depression-like behaviors as recently observed in rodent models of learned helplessness (Shumake et al, 2005), brain-derived neurotrophic factor knockout mice (Heldt et al, 2007), and serotonin transporter knockout mice (Wellman et al, 2007). These findings suggested that depression increases susceptibility to persistent fear typical of anxiety disorders, and vice versa, persistent fear might contribute to depression.…”

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

“…Studies of predatorstress based models of PTSD have also found that BDNF expression is regulated by exposure to traumatic stimuli long after the fear-inducing stimulus has passed (Kozlovsky et al, 2007;Ou and Gean, 2007), indicating that BDNF regulation may be important for the persistence of pathological fear. Indeed, extinction of conditioned fear involves exon-specific regulation of BDNF gene expression in the prefrontal cortex (Bredy et al, 2007) and deletion of the BDNF gene specifically in the hippocampus impaired fear learning and impaired the extinction of conditioned fear (Heldt et al, 2007), implicating BDNF as a potential target for regulating the erasure of maladaptive fear responses.…”