Memory  >   Memory Extinction: The Role of BDNF

Infusion of brain-derived neurotrophic factor (BDNF) into the infralimbic cortex is capable of inducing fear extinction (Peters et al., 2010). Hippocampal-specific deletion of the BDNF gene significantly reduced extinction of conditioned fear (Heldt et al., 2007). Therefore, BDNF in both cortex and hippocampus has the capacity to cause memory extinction. A simple mechanism is proposed below.

Prevention of GluN2B-NMDARs from Internalization

In the cytoplasmic domain of the GluN2B subunit of NMDA receptors (NMDARs), there are three tyrosine residues (abbreviated as "Y") which can be phosphorylated by Fyn. Phosphorylation at Y1472 prevents GluN2B-containing NMDARs from being internalized (Prybylowski et al., 2005; Chen and Roche, 2007), consequently increasing their localization to the plasma membrane. GluN2B-containing NMDARs are subject to NMDAR extinction, which underlies the macroscopic memory extinction (Chapter 19). Therefore, phosphorylation of GluN2B at Y1472 may promote memory extinction. BDNF signaling has been shown to enhance Y1472 phosphorylation by activating Fyn (see Paper 25).

Tet1 also plays an important role in memory extinction (Rudenko et al., 2013), but its actions could be mediated by BDNF. Tet1 is an enzyme that catalyzes DNA demethylation which is often used to regulate gene expression. Tet1 has been demonstrated to regulate the expression of the BDNF gene (Hsieh et al., 2016; Keifer, 2017).

This mechanism is further supported by the following two reports:

  • Valproic acid, a histone deacetylase inhibitor, potentiates memory extinction by increasing the expression of BDNF (Bredy et al., 2007).
  • Vorinostat, another histone deacetylase inhibitor, facilitates fear extinction by enhancing the expression of the hippocampal GluN2B (NR2B) gene (Fujita et al., 2012).

Reconsolidation or Extinction

Retrieval of a consolidated memory can cause the memory to become labile and lead to either reconsolidation (strengthening) or extinction. A brief reexposure to the reminding cues tends to induce reconsolidation whereas a prolonged reexposure triggers memory extinction (de la Fuente et al., 2011). It has been demonstrated that memory extinction requires calcineurin (CaN) to activate the transcription factor, nuclear factor of activated T-cells (NFAT). BDNF is a key target of NFAT (Groth and Mermelstein, 2003; Groth et al., 2007; Vashishta et al., 2009). In contrast, reconsolidation requires the transcription factor, NF-κB, which targets many genes involved in spinogenesis and synaptic strengthening (de la Fuente et al., 2015; Engelmann and Haenold, 2016).

Recalling that brief tetanic stimulation induces long-term potentiation (LTP) whereas prolonged low frequency stimulation induces long-term depression (LTD) (Chapter 18). This is because CaN is anchored to GluN2B-NMDARs which have slower kinetics than GluN2A-NMDARs. The same property also explains why prolonged reexposure to reminding cues triggers CaN signaling. The CaN activity depends on Ca2+. Therefore, the Ca2+ influx through GluN2B-NMDARs should favor extinction. Several pathways may activate NF-κB to promote reconsolidation, such as the metabotropic glutamate receptor subtype 5 (mGluR5) (O'Riordan et al., 2006; Wang and Zhuo, 2012) and α1-adrenergic receptor (Perez et al., 2009).

The Mechanism of Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is characterized by the inability to forget or extinguish traumatic events. It has been demonstrated to associate with several proteins, including BDNF, glucocorticoid, mGluR5 and α1-adrenergic receptor. As expected, lower BDNF level is prone to develop PTSD (Angelucci et al., 2014; Su et al., 2015; Stratta et al., 2016). Activation of glucocorticoid receptors has been shown to suppress BDNF expression (Suri and Vaidya, 2013; Wosiski-Kuhn et al., 2014). This may account for the link between PTSD and enhanced glucocorticoid receptor responsiveness (Yehuda et al., 2009). In PTSD, mGluR5 is upregulated (Holmes et al., 2017), which could over-activate NF-κB (O'Riordan et al., 2006; Wang and Zhuo, 2012) to strengthen the traumatic memory. α1-adrenergic receptor is also implicated in PTSD, possibly via its capacity to activate NF-κB (Perez et al., 2009). Its antagonist, Prazosin, has been used for the treatment of PTSD (De Berardis et al., 2015).


Figure 22-1. The proposed signaling cascades leading to PTSD.


Author: Frank Lee
First published: October, 2017
Last updated: November 9, 2018