Postsynaptic BDNF signalling regulates long‐term potentiation at thalamo‐amygdala afferents

Abstract

Non-technical summary Long-term potentiation (LTP) in the lateral amygdala (LA) is a widely accepted cellular correlate of fear learning. In the present study we analysed the involvement of the neurotrophin brain-derived neurotrophic factor (BDNF) in amygdala LTP by stimulating selectively thalamic or cortical sensory inputs into the LA. In heterozygous BDNF knockout mice we observed that LTP in the cortico-amygdala pathway remained intact, whereas LTP in the thalamo-amygdala pathway was abolished. Likewise, acute interference with BDNF/TrkB signalling in wild-type mice by application of a BDNF scavenger (TrkB-IgG) led to inhibition of LTP in this pathway. In addition, postsynaptic inhibition of TrkB receptors, which mediate BDNF effects, blocked LTP in the thalamic pathway. Thus, our data demonstrate for the first time a crucial role for postsynaptic BDNF signalling in mediating LTP selectively in the thalamo-amygdala pathway in the LA.Abstract The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in the hippocampus and the neocortex of the mammalian brain. In contrast, a role of BDNF in mediating synaptic plasticity and fear learning in the amygdala is just beginning to evolve. Using patch clamp recordings from projection neurons of the dorsal lateral amygdala (LA) in acute slices of mice, we now investigated the cellular mechanism of BDNF-mediated long-term potentiation (LTP) of excitatory postsynaptic currents (EPSCs) in the amygdala. LTP was elicited in cortical and thalamic synaptic inputs by pairing postsynaptic depolarisation with presynaptic stimulation. LTP in the cortico-amygdala pathway was not changed in heterozygous BDNF-knockout (BDNF +/− ) mice. In contrast, pairing induced LTP in the thalamic input was abolished in BDNF +/− mice (BDNF +/− : 104.0 ± 5.7% of initial EPSC values; WT: 132.5 ± 7.3%). Likewise, inhibition of BDNF/TrkB signalling with TrkB-IgGs as scavenger molecules for endogenous BDNF blocked LTP in wild-type mice in this pathway control: 132.5 ± 8.7%). Inclusion of the tyrosine kinase inhibitor K252a in the pipette solution also prevented the induction of LTP in the thalamic pathway, indicating a postsynaptic site of action of BDNF in regulating LTP. Reduced BDNF levels in BDNF +/− mice did not affect intrinsic membrane properties of LA projection neurons. Likewise, presynaptic glutamate release, and postsynaptic membrane properties also remained unaffected in BDNF +/− mice. These data suggest a postsynaptic site of action of BDNF in mediating LTP selectively in the thalamic fear conditioning pathway.

Growth factor signaling and memory formation: temporal and spatial integration of a molecular network

“…After training, an IGF2 injection is capable of enhancing IA memory if injected into the hippocampus, but not the amygdala (Chen et al 2011), suggesting that although both the hippocampus and amygdala are important for IA memory, IGF2 is selectively recruited by the hippocampus in this task. BDNF is an important regulator of hippocampal plasticity and hippocampus-dependent memory, but can also modulate amygdala-dependent plasticity (Rattiner et al 2004(Rattiner et al , 2005Meis et al 2012). Indeed, BDNF signaling is required for LTP induced in thalamus -amygdala connections, but is not required for LTP induced at cortex -amygdala connections (Meis et al 2012), suggesting that BDNF may have varied, but restricted, roles in different brain regions.…”

“…BDNF is an important regulator of hippocampal plasticity and hippocampus-dependent memory, but can also modulate amygdala-dependent plasticity (Rattiner et al 2004(Rattiner et al , 2005Meis et al 2012). Indeed, BDNF signaling is required for LTP induced in thalamus -amygdala connections, but is not required for LTP induced at cortex -amygdala connections (Meis et al 2012), suggesting that BDNF may have varied, but restricted, roles in different brain regions. Interestingly, in an object recognition task, BDNF release is increased following training and after 24-h testing in both the dentate gyrus and perirhinal cortex (Callaghan and Kelly 2012).…”

Age-dependent deficits in fear learning in heterozygous BDNF knock-out mice

“…The neurotrophin BDNF (brain-derived neurotrophic factor) is not only important for neuronal survival and differentiation in the developing brain, but it is also a crucial mediator for the induction and maintenance of synaptic plasticity (e.g., long-term potentiation), thereby modulating learning processes (see e.g., Lessmann et al 2003;Bekinschtein et al 2008;Gottmann et al 2009;Cowansage et al 2010;Yoshii and Constantine-Paton 2010;Meis et al 2012). It was demonstrated recently that BDNF signaling is also involved in cued fear learning.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…Recently, in heterozygous BDNF-knockout (BDNF+/−) mice it has been demonstrated that the reduced BDNF levels did not affect presynaptic glutamate release (Meis et al, 2012).…”