Essential role of brain-derived neurotrophic factor in adult hippocampal function

Abstract

Brain-derived neurotrophic factor (BDNF) regulates neuronal development and function. However, it has been difficult to discern its role in the adult brain in influencing complex behavior. Here, we use a recently developed inducible knockout system to show that deleting BDNF in broad forebrain regions of adult mice impairs hippocampal-dependent learning and long-term potentiation. We use the inducible nature of this system to show that the loss of BDNF during earlier stages of development causes hyperactivity and more pronounced hippocampal-dependent learning deficits. We also demonstrate that the loss of forebrain BDNF attenuates the actions of desipramine, an antidepressant, in the forced swim test, suggesting the involvement of BDNF in antidepressant efficacy. These results establish roles for BDNF in the adult, and demonstrate the strength of this inducible knockout system in studying gene function in the adult brain.B rain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors (1, 2). It is widely expressed in the mammalian brain (3) and regulates many aspects of neuronal function (4-8). However, a role for BDNF in regulating complex behavior has been difficult to assess, because of the lack of specific pharmacological agents and the early postnatal lethality of BDNF null (Ϫ͞Ϫ) mice (9). Studies examining heterozygous BDNF (ϩ͞Ϫ) mice, which display roughly half the normal levels of BDNF in brain, have reported increased feeding behavior, obesity, hyperactivity, and aggressiveness (10-12). However, these alterations may arise from developmental abnormalities and complicate the interpretation of the role of BDNF in the adult brain.The recent generation of conditional BDNF knockout (KO) mice circumvents the problem of postnatal lethality and allows for some regional specificity of gene deletion. For example, conditional BDNF KO mice survive to adulthood and exhibit a range of deficits similar to those seen in the heterozygous null mice (13). However, such conditional KO mice still suffer from the fact that they delete a gene of interest during late-embryonic or early postnatal periods and thus do not preclude developmental abnormalities as the cause of behavioral impairments observed. This is of a particular concern in studying complex behavior because early developmental periods in humans are crucial for the manifestation of many complex neuropsychiatric illnesses. To truly investigate the influence of BDNF on complex behavior in adults, it is necessary to have a system in which BDNF is deleted in an inducible manner in specific brain regions. We have generated an inducible KO system in which BDNF can be deleted selectively in the brain of adult mice. Here we describe the phenotype of mice in which BDNF has been deleted in broad forebrain regions of adult mice. We use the inducibility of the system to examine the phenotype of mice in which BDNF has been deleted at earlier stages of development in the same brain regions. Our results demonstrate that the role of BDNF in the ...

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

“…15 In addition, behavioral deficits are more pronounced in mice with embryonic than adult ablation of BDNF. 11 These data suggest that BDNF requirement of neurons may change from development to adulthood, and mice with embryonic and adult deletion of BDNF may exhibit markedly different neocortical transcriptome profiles.…”

“…11,12 To generate the animals for the current experimental series, two geneticallyaltered, independently-derived mouse strains were used. Reduction of BDNF expression was achieved using an inducible knockout (KO) of the BDNF gene where two transgenes, the tetracycline transactivator (tTA) gene driven by neuron-specific enolase (NSE) promoter (nse-tTA) 16 and the Cre recombinase gene under the control of tTA-responsive tetO promoter (tetO-cre) 17,18 regulate the deletion of floxed exon V of BNDF 19 in a tetracycline-dependent manner.…”

“…Maximum recombination was achieved 4 weeks after doxycycline removal 11 resulting in a > 70% reduction in BDNF transcript and protein levels. 11,12 Littermates with NSE-tTA and tetO-cre transgenes were used as controls. These mice expressed similar levels of BDNF as wild type mice.…”

“…These mice expressed similar levels of BDNF as wild type mice. 11 Mice with BDNF deletion induced from embryogenesis or in adulthood, together with the corresponding control animals, were sacrificed between 5 and 6 months of age. The experimental series consisted of frontal cortices from a total of 38 animals with different animals used for each method of gene expression analysis.…”

“…However, the dependence of different subclasses of GABA neurons on BDNF signaling remains to be determined. For example, the inducible deletion of BDNF 11 does not result in altered mRNA levels of the 67 kDa isoform of glutamic acid decarboxylase (GAD1) or parvalbumin (PARV) in adult mice. 12 Furthermore, the dependence of any given neuronal type on BDNF may differ as a function of developmental stage.…”