Impairments in High-Frequency Transmission, Synaptic Vesicle Docking, and Synaptic Protein Distribution in the Hippocampus of BDNF Knockout Mice

Abstract

Brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) at hippocampal CA1 synapses by a presynaptic enhancement of synaptic transmission during highfrequency stimulation (HFS). Here we have investigated the mechanisms of BDNF action using two lines of BDNF knockout mice. Among other presynaptic impairments, the mutant mice exhibited more pronounced synaptic fatigue at CA1 synapses during high-frequency stimulation, compared with wild-type animals. Quantitative analysis of CA1 synapses revealed a significant reduction in the number of vesicles docked at presynaptic active zones in the mutant mice. Synaptosomes prepared from the mutant hippocampus exhibited a marked decrease in the levels of synaptophysin as well as synaptobrevin [vesicle-associated membrane protein (VAMP-2)], a protein known to be involved in vesicle docking and fusion. Treatment of the mutant slices with BDNF reversed the electrophysiological and biochemical deficits in the hippocampal synapses. Taken together, these results suggest a novel role for BDNF in the mobilization and/or docking of synaptic vesicles to presynaptic active zones.

Maintenance Treatment with Fluoxetine is Necessary to Sustain Normal Levels of Synaptic Markers in an Experimental Model of Depression: Correlation with Behavioral Response

“…Moreover, chronic treatment with FLX promotes BDNF expression in the rat hippocampus (De Foubert et al, 2004) that in turn leads to activation of genes and biochemical pathways involved in plasticity and survival (Mattson et al, 2004). At synaptic structural level, adult BDNF knockout mice show reduced number of vesicles docked at presynaptic active zones and marked decreased levels of SYN and synaptobrevin (Pozzo-Miller et al, 1999), alterations that can be reversed by BDNF administration (Pozzo-Miller et al, 1999), and somewhat resemble the synaptic protein decrease we observed in LH animals. On the other hand, Figure 7 Persistence of NLF diminution after fluoxetine (FLX) withdrawal.…”

“…At this level, experimental evidences point out once again to BDNF as an appealing candidate. Besides its role in synaptogenesis Hu et al, 2005) and synaptic ultra structural composition (Pozzo-Miller et al, 1999;Tartaglia et al, 2001;Tyler and Pozzo-Miller, 2001;Carter et al, 2002) in developing and adult brain, this neurotrophin promotes synaptic connectivity by modulating maturation of developing synapses in culture (Collin et al, 2001) and by stabilizing in vivo synapses already established (Hu et al, 2005). Taken into account that BDNF has been proposed to mediate FLX action, it can be hypothesized that antidepressant withdrawal might drop down BDNF levels to the abnormally low concentrations described in stressed animals leading to the reversion of synaptic changes we observed under FLX treatment.…”

Neurotrophin signaling among neurons and glia during formation of tripartite synapses

“…Consistent with these observations, several groups report that BDNF treatment of hippocampal and cortical neuronal cultures increase synaptobrevin expression (Takei et al, 1997;Tartaglia et al, 2001;Yamada et al, 2002). In accordance with the effects of exogenous neurotrophins, mice that are deficient in either BDNF or TrkB exhibit marked reductions in the total number of docked vesicles at hippocampal synapses and a redistribution of docked vesicles to areas far from the active zone in the cerebellar synapses (Martinez et al, 1998;Pozzo-Miller et al, 1999;. Moreover, hippocampal sections from TrkB-deficient mice exhibit an overall reduction in syntaxin 1 and SNAP25 immunoreactivity (Martinez et al, 1998).…”

“…At hippocampal and cortical synapses in vivo and in vitro, BDNF facilitates long-term potentiation, attenuates long-term depression and promotes homeostatic and competitive interactions that refine neural circuitry (Korte et al, 1995;Akaneya et al, 1996;Cabelli et al, 1996;Huang et al, 1999;Turrigiano and Nelson, 2000;Turrigiano and Nelson, 2004). At hippocampal and cerebellar synapses in BDNF-deficient mice, high-frequency stimulation and paired-pulse facilitation are impaired, which is consistent with compromised presynaptic release (Pozzo-Miller et al, 1999;Carter and Regehr, 2002). These studies demonstrate that BDNF acts presynaptically to modulate the dynamics of glutamate release at developing and mature synapses.…”

“…Neurotrophins might modulate either the assembly or the stabilization of synaptic vesicles through post-translation modifications of SNARE complex proteins (Vicario-Abejon et al, 1998;Pozzo-Miller et al, 1999;Tartaglia et al, 2001). Consistent with this hypothesis, BDNF-deficient mice exhibit decreased synaptosomal levels of the vesicular proteins synaptobrevin and synaptophysin, although levels form whole hippocampal extracts appear to be similar to controls (Pozzo-Miller et al, 1999).…”