Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism

Abstract

Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF(Met/Met)) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF(Met/Met) mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild-type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF(Met/Met) mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers.

The Role of BDNF in the Development of Fear Learning

“…ProBDNF and mature BDNF utilize distinct receptors to mediate divergent neuronal functions suggesting that the two isoforms may also exhibit a differential expression pattern in the developing brain. To address this question, Hempstead and colleagues have generated a knock‐in mouse in which wild‐type (WT) BDNF is expressed with a C‐terminal hemagglutinin (HA) epitope tag ( Bdnf‐HA ) to enhance BDNF protein detection .…”

Activity-dependent signaling: influence on plasticity in circuits controlling fear-related behavior

“…Abnormal NMDAR-mediated transmission in AMY, HPC and PFC contributes to altered synaptic plasticity in mice modeling the BDNF Val66Met polymorphism [55–57]. Decreased late phase long-term potentiation (LLTP) hippocampal plasticity is also observed in animals where activity-dependent BDNF signaling is selectively attenuated [38].…”

The BDNF Val66Met polymorphism enhances glutamatergic transmission but diminishes activity-dependent synaptic plasticity in the dorsolateral striatum

“…Our earlier studies have demonstrated an impairment of synaptic plasticity in the hippocampus, the medial prefrontal cortex and the amygdala by the BDNF Val66Met polymorphism (Bath et al, 2012; Galvin et al, 2015; Ninan et al, 2010; Pattwell et al, 2012). Since corticostriatal plasticity depends upon BDNF-TrkB signaling (Jia et al, 2010), we asked whether the BDNF Val66Met affects synaptic plasticity in the dorsal striatum.…”

“…Consistently, the BDNF Val66Met SNP impairs synaptic plasticity in the infralimbic medial prefrontal cortex, the hippocampus and the central amygdala (Bath et al, 2012; Galvin et al, 2015; Ninan et al, 2010; Pattwell et al, 2012). However, it is unknown whether the Val66Met affects synaptic function in the corticostriatal pathway, the impairment of which has been implicated in not only anxiety disorders but also drug abuse (Fumagalli et al, 2007; Furman et al, 2011; Im et al, 2010; Jeanblanc et al, 2009; McGough et al, 2004; Pittenger et al, 2011).…”