Role of activity-dependent BDNF expression in hippocampal–prefrontal cortical regulation of behavioral perseverance

Abstract

Activity-dependent gene transcription, including that of the brainderived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal-PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders.

Hippocampal–Prefrontal BDNF and Memory for Fear Extinction

“…Previous studies have shown that hippocampal BDNF is necessary for fear extinction (Heldt et al, 2007;Sakata et al, 2013). Our immunocytochemical results showed that extinction increased BDNF levels in vHPC and BA, but not in mPFC or central amygdala.…”

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

“…Previous efforts to understand the functional significance of individual transcripts focused exclusively on promoter IV because of its established role in activity-dependent transcription (Gao et al, 2014;Hong et al, 2008;Martinowich et al, 2011;Sakata et al, 2013;Sakata et al, 2009). These studies determined that loss of BDNF expression from promoter IV is sufficient to generate specific behavioral and cellular effects, but whether loss from other Bdnf promoters caused similar impairments was not studied (Gao et al, 2014;Hong et al, 2008;Martinowich et al, 2011;Sakata et al, 2013;Sakata et al, 2009). To address the outstanding question of whether BDNF produced from different promoters governs discrete molecular, cellular, and behavioral functions, we generated a novel set of transgenic mice in which BDNF production from promoters I, II, IV, or VI is selectively disrupted.…”

“…As a secreted neurotrophic factor, BDNF regulates diverse biological functions that range from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult (Andero et al, 2014;Autry and Monteggia, 2012;Castren, 2014;Chao et al, 2006;Lu, 2003). Mice engineered to disrupt BDNF signaling display several phenotypes, including hyperphagia-induced obesity, enhanced aggression, changes in cognitive behavior, and blunted response to antidepressant treatments (Autry et al, 2011;Chan et al, 2006;Ito et al, 2011;Lyons et al, 1999;Monteggia et al, 2004;Monteggia et al, 2007;Sakata et al, 2013). In line with BDNF's ability to influence multiple pathways, markers of 5-HT signaling as well as GABAergic transmission are altered in these models (Deltheil et al, 2008;Guilloux et al, 2012;Homberg et al, 2014;Hong et al, 2008;Huang et al, 1999;Luellen et al, 2007;Martinowich and Lu, 2008;Rios et al, 2006;Sakata et al, 2009;Tripp et al, 2012).…”

“…Moreover, a selective deletion of BDNF exons I-III that spares the remaining portion of the gene is sufficient to cause obesity in humans (Han et al, 2008). In mice, selective BDNF disruption from promoter IV, which significantly contributes to activity-dependent BDNF production, leads to impaired GABAergic transmission and behavioral perseverance (Gao et al, 2014;Hong et al, 2008;Martinowich et al, 2011;Sakata et al, 2013;Sakata et al, 2009). …”

Brain derived neurotrophic factor mediated learning, fear acquisition and extinction as targets for developing novel treatments for anxiety

“…: Morris water maze). In addition, the fear conditioning When comparing mutant mice with a selective disruption of activity-dependent Bdnf expression to not genetically manipulated mice, Sakata et al 27 showed that mutant mice are more prone to behavioral perseveration, including perseveration of conditioned fear responses due to impairment in extinction retention. Those animals exhibited selective impairment of Bdnf-dependent but not Bdnf-independent late LTP in the hippocampus.…”