Spermidine improves the persistence of reconsolidated fear memory and neural differentiation in vitro: Involvement of BDNF

Abstract

Putrescine, spermidine and spermine are organic cations implicated in learning, memory consolidation, reconsolidation and neurogenesis. These physiological processes are closely related, and convincing evidence indicates that neurogenesis is implicated both, in the establishment and maintenance of remote contextual fear memory. Although brain-derived neurotrophic factor (BDNF) is a key mediator involved in both neurogenesis and memory consolidation, effects of spermidine on persistence of memory after reactivation (reconsolidation) and possible involvement of BDNF have not been investigated. Here, we investigated whether the intrahippocampal infusion of spermidine improves the persistence of reconsolidated contextual fear conditioning memory in rats and whether these possible changes depend on BDNF/TrkB signaling in the hippocampus. The infusion of spermidine immediately and 12h post-reactivation improved fear memory of the animals tested seven but not two days after reactivation. The facilitatory effect of spermidine on the persistence of reconsolidated memory was blocked by the TrkB inhibitor ANA-12 (73.6pmol/site) and accompanied by mature BDNF level increase in the hippocampus, indicating that it depends on the BDNF/TrkB pathway. We also investigated whether spermidine alters BDNF levels and neural progenitor cell differentiation in vitro. Spermidine increased BDNF levels in vitro, facilitating neuritogenesis and neural migration. Spermidine-induced neuritogenesis in vitro was also blocked by ANA-12 (10µM). Since spermidine increases BDNF levels and facilitates neural differentiation in vitro, similar mechanisms may be involved in spermidine-induced facilitation of the persistence of reconsolidated memory.

Polyamines: Functions, Metabolism, and Role in Human Disease Management

“…Fabbrin et al [ 133 ] reported an improvement in fear memory consolidation post spermidine treatment (2 nmol/site) given immediately after training in adult male Wistar rats, whereas ANA-12, a TrkB antagonist, inhibited the positive effect of spermidine on memory consolidation. Signor et al [ 134 ], in a series of experiments on rats to study the effect of spermidine consumption on fear memory reconsolidation and neural differentiation, noted that reconsolidated memory persistence increased in a time-dependent manner when spermidine is administered (intrahippocampal infusion (i.h.)) immediately ( p = 0.005) or 12 h ( p = 0.007) post reactivation session ( p = 0.005), as the freezing score increased to ~80% and ~65%, respectively, as compared to ~40% in the control group during the testing session conducted 7 days post reactivation.…”

“…Additionally, in vitro studies revealed that as a consequence of spermidine treatment (10 nM), the migration of neurons increased on day 1 of differentiation, while neurites count increased on day 7 of differentiation of neural progenitor cells (NPCs) without affecting their length. Signor et al [ 134 ] reported the involvement of GluN2B-containing N -methyl-D-aspartate (NMDA) receptors, protein synthesis, and role of protein kinase A (PKA) pathway in increasing persistence of fear memory when spermidine is administered (i.h.) 12 h after training.…”

On the Involvement of BDNF Signaling in Memory Reconsolidation

“…In agreement with these results, reactivation-induced fear conditioning memory enhancement requires hippocampal BDNF expression in stressed rats (Giachero et al, 2013). Also, post-retrieval intra-CA1 spermidine administration lengthens contextual fear memory duration through a mechanism that depends on hippocampal BDNF maturation as well as on the interaction between this neurotrophin and its main receptor, tropomyosin-related receptor kinase B (TrkB; Signor et al, 2017). Further, increased BDNF mRNA and protein levels as well as TrkB activation in the insular cortex accompany hippocampus-independent conditioned taste aversion (CTA) memory retrieval, and interfering with BDNF synthesis in this cortex after reactivation causes amnesia.…”

“…In this respect, it was recently proposed that enhancing reconsolidation of extinction memory could be a viable strategy to avoid its decay (Radiske et al, 2015; Rosas-Vidal et al, 2015). Findings from the last decade show that BDNF modulates reconsolidation of both aversive and extinction memories (Wang et al, 2012; Giachero et al, 2013; Radiske et al, 2015; Signor et al, 2017). Overall, these studies suggest that drugs interfering with BDNF signaling during reconsolidation of aversive memories could help to impair its retention, while approaches that activate BDNF/TrkB pathways after extinction memory retrieval may promote its persistence, preventing reappearance of the fear response.…”

Chemical activation of SAT1 corrects diet-induced metabolic syndrome

“…Beyond its longevity-extending effects, spermidine has rather broad health-promoting effects. Thus, it improves diastolic function of the aging heart, prevents heart failure driven by salt-induced hypertension [2], improves the efficacy of anticancer immunotherapies [9,10], increases cognition [11], halts inflammation [12], reduces liver fibrosis and nonalcoholic fatty liver disease (NAFLD) [6,13], and prevents high-fat diet (HFD)-induced obesity and diabetes [14]. Many of these effects depend on the induction of autophagy [5,6,9,10,14].…”