The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced.

Brain-derived neurotrophic factor (BDNF) heterozygous knockout mice (BDNF^+/− mice) show fear learning deficits from 3 months of age onwards. Here, we addressed the question how this learning deficit correlates with altered long-term potentiation (LTP) in the cortical synaptic input to the lateral amygdala (LA) and at downstream intra-amygdala synapses in BDNF^+/- mice. Our results reveal that the fear learning deficit in BDNF^+/− mice was not paralleled by a loss of LTP, neither at cortical inputs to the LA nor at downstream intra-amygdala glutamatergic synapses. As we did observe early fear memory (30 min after training) in BDNF^+/− mice while long-term memory (24 h post-training) was absent, the stable LTP in cortico-LA and downstream synapses is in line with the intact acquisition of fear memories. Ex vivo recordings in acute slices of fear-conditioned wildtype (WT) mice revealed that fear learning induces long-lasting changes at cortico-LA synapses that occluded generation of LTP 4 and 24 h after training. Overall, our data show that the intact LTP in the tested amygdala circuits is consistent with intact acquisition of fear memories in both WT and BDNF^+/− mice. In addition, the lack of learning-induced long-term changes at cortico-LA synapses in BDNF^+/− mice parallels the observed deficit in fear memory consolidation.

Neurotrophins are secreted proteins that control survival, differentiation, and synaptic plasticity. While mature neurotrophins regulate these functions via tyrosine kinase signaling (Trk), uncleaved pro-neurotrophins bind preferentially to the p75 neurotrophin receptor (p75^NTR) and often exert opposite effects to those of mature neurotrophins. In the amygdala, brain-derived neurotrophic factor (BDNF) enables long-term potentiation as well as fear and fear extinction learning. In the present study, we focused on the impact of mature BDNF and proBDNF signaling on long-term depression (LTD) in the lateral amygdala (LA). Hence, we conducted extracellular field potential recordings in an in vitro slice preparation and recorded LTD in cortical and thalamic afferents to the LA. LTD was unchanged by acute block of BDNF/TrkB signaling. In contrast, LTD was inhibited by blocking p75^NTR signaling, by disinhibition of the proteolytic cleavage of proBDNF into mature BDNF, and by preincubation with a function-blocking anti-proBDNF antibody. Since LTD-like processes in the amygdala are supposed to be related to fear extinction learning, we locally inhibited p75^NTR signaling in the amygdala during or after fear extinction training, resulting in impaired fear extinction memory. Overall, these results suggest that in the amygdala proBDNF/p75^NTR signaling plays a pivotal role in LTD and fear extinction learning.

Brain-derived neurotrophic factor (BDNF) has previously been shown to play an important role in glutamatergic synaptic plasticity in the amygdala, correlating with cued fear learning. While glutamatergic neurotransmission is facilitated by BDNF signaling in the amygdala, its mechanism of action at inhibitory synapses in this nucleus is far less understood. We therefore analyzed the impact of chronic BDNF depletion on GABA_A-mediated synaptic transmission in BDNF heterozygous knockout mice (BDNF^+/−). Analysis of miniature and evoked inhibitory postsynaptic currents (IPSCs) in the lateral amygdala (LA) revealed neither pre- nor postsynaptic differences in BDNF^+/− mice compared to wild-type littermates. In addition, long-term potentiation (LTP) of IPSCs was similar in both genotypes. In contrast, facilitation of spontaneous IPSCs (sIPSCs) by norepinephrine (NE) was significantly reduced in BDNF^+/− mice. These results argue against a generally impaired efficacy and plasticity at GABAergic synapses due to a chronic BDNF deficit. Importantly, the increase in GABAergic tone mediated by NE is reduced in BDNF^+/− mice. As release of NE is elevated during aversive behavioral states in the amygdala, effects of a chronic BDNF deficit on GABAergic inhibition may become evident in response to states of high arousal, leading to amygdala hyper-excitability and impaired amygdala function.