Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Abstract

Caffeine has cognitive‐enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor‐independent form of LTP (CAFLTP) in the CA1 region of the hippocampus by promoting calcium‐dependent secretion of BDNF, which subsequently activates TrkB‐mediated signaling required for the expression of CAFLTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAFLTP, a process that requires cytosolic free Ca2+. Consistent with the involvement of IRS2 signals in caffeine‐mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2−/− mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3‐kinase (PI3K) pathway. These findings indicate that TrkB‐IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.

The physiology of regulated BDNF release

“…2b ). Similarly, GPCR-mediated BDNF release was also only dependent on calcium release from internal calcium stores (Buldyrev et al 2006 ; Canossa et al 2001 ; Lao-Peregrin et al 2017 ; Santi et al 2006 ). In addition, intracellular application of the non-hydrolysable guanosine diphosphate (GDP) analog GDPβ-S inhibits giant depolarization (GDP)-induced BDNF release (Kuczewski et al 2008 ).…”

“…In addition, intracellular application of the non-hydrolysable guanosine diphosphate (GDP) analog GDPβ-S inhibits giant depolarization (GDP)-induced BDNF release (Kuczewski et al 2008 ). In neuronal preparations, GCPRs activated by caffeine, glutamate via mGluR, GABA via GABA B receptors, or calcitonin-gene-related protein (CGRP) receptor via CGRP have been shown to induce release of BDNF (Balkowiec and Katz 2002 ; Buldyrev et al 2006 ; Canossa et al 2001 ; Lao-Peregrin et al 2017 ; Santi et al 2006 ). Nevertheless, GPCR-mediated release seems to be even more prominent in non-neuronal cells.…”

Botanicals as Modulators of Neuroplasticity: Focus on BDNF

“…Three studies investigated the in vitro effect of caffeine on BDNF. In particular, caffeine upregulated the BDNF protein levels in mouse hippocampal slices (100 μ M for 5 minutes) [ 34 ], increased the BDNF release in hippocampal neurons [ 35 ], and efficiently stimulated the BDNF isoform I and IV expression in the presence of KCl (10 mM) in cortical neurons [ 36 ].…”

Segregation of caffeine reward and aversion in the rat nucleus accumbens shell versus core

“…Over 89% of adults in the United States consume caffeine regularly (Fulgoni, Keast, & Lieberman, 2015). Though direct comparisons of caffeine consumption between people and rodents ought to be made with caution and with consideration of the higher metabolic functions in rodents, it is estimated that 1 cup of coffee is roughly equivalent to a dose of 2.3–5 mg/kg in rodents (Fredholm et al, 1999; Lao‐Peregrin et al, 2016). Our data, then, represent a range of caffeine consumed by people of around 0.4–6 cups of coffee, and suggest that caffeine's motivational effects at these doses are mediated by mesolimbic dopaminergic pathways.…”