Impact of Chronic BDNF Depletion on GABAergic Synaptic Transmission in the Lateral Amygdala

Abstract

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 GABAA-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.

Neurotrophin signalling in amygdala-dependent cued fear learning

“…Nevertheless, BDNF +/− mice displayed neither impaired basal synaptic GABAergic transmission nor altered inhibitory synaptic plasticity in the LA. However, positive modulation of interneuron activity by noradrenaline was significantly decreased by chronic BDNF reduction (Meis et al 2019). In line with these results, BDNF depletion also abolished facilitation of synaptic GABAergic transmission by serotonin (Daftary et al 2012).…”

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

“…During the critical period of sensory system maturation, neuronal activity (due to sensory experience) is likely to be important, not only for the termination of the migration of cortical INs, but also for their proper integration into functional circuits ( de Villers-Sidani et al, 2007 ; Lim et al, 2018 ). There is agreement that an activity-dependent release of BDNF from pyramidal neurons is required to sculpt the integration of the cortical PV-IN network in nearly all sensory cortices, probably by driving cortical tonic inhibition through synaptogenesis of peri-somatic PV-INs with pyramidal neurons ( Hong et al, 2008 ; Xu et al, 2010 ; Griffen and Maffei, 2014 ; Lim et al, 2018 ; Meis et al, 2019 ). The proper integration of GABAergic INs into higher cortical sensory regions is essential for proper feed-forward inhibition, the sharpening of receptive fields, and pattern separation ( Pouille and Scanziani, 2001 ; Leutgeb et al, 2007 ).…”

Neonatal Tactile Stimulations Affect Genetic Generalized Epilepsy and Comorbid Depression-Like Behaviors

“…When BDNF is released from corticostriatal neurons and is bound to the tyrosin kinase tropomyosin-related kinase B receptors, multiple intracellular pathways are activated, as a result of which neurite growth, synaptic plasticity, proliferation, and survival are controlled ( Castrén and Rantamäki, 2010 ; Yoshii and Constantine-Paton, 2010 ). It should be emphasized that BDNF is involved in the maturation of inhibitory GABAergic synapses ( Henneberger et al, 2002 ; Yamada et al, 2003 ; Berghuis et al, 2004 ; Zhu et al, 2019 ), as well as that maturation and functioning of excitatory and inhibitory transmission is also modulated differently by BDNF ( Gottmann et al, 2009 ; Meis et al, 2019 ). Moreover, it has been shown that early NTS treatment leads to increase in the skin and the brain production of FGF-2 ( Richards et al, 2012 ).…”