A simple role for BDNF in learning and memory?

Abstract

Since its discovery almost three decades ago, the secreted neurotrophin brain-derived neurotrophic factor (BDNF) has been firmly implicated in the differentiation and survival of neurons of the CNS. More recently, BDNF has also emerged as an important regulator of synaptogenesis and synaptic plasticity mechanisms underlying learning and memory in the adult CNS. In this review we will discuss our knowledge about the multiple intracellular signalling pathways activated by BDNF, and the role of this neurotrophin in long-term synaptic plasticity and memory formation as well as in synaptogenesis. We will show that maturation of BDNF, its cellular localization and its ability to regulate both excitatory and inhibitory synapses in the CNS may result in conflicting alterations in synaptic plasticity and memory formation. Lack of a precise knowledge about the mechanisms by which BDNF influences higher cognitive functions and complex behaviours may constitute a severe limitation in the possibility to devise BDNF-based therapeutics for human disorders of the CNS.

Keywords: BDNF; behaviour; cell signalling; learning and memory; synaptic plasticity; synaptogenesis.

Figure 1

Mouse and rat Bdnf gene structure and transcripts. Exons are indicated by boxes. Filled box in exon IXA indicates the coding region of the Bdnf gene. Lines indicate splice variants. Arrows indicate within-exon splice sites and alternative polyadenylation sites. The Bdnf gene is transcribed from different promoters, immediately preceding each of the 5´ exons (exons I–VIII), so that each full-length transcript contains a unique 5´-exon and a common 3´-exon (exon IXA) that encodes the BDNF protein. Transcript BDNF6B results from splicing events that incorporate exons VII, VIII and IXA.

Figure 2

BDNF processing, packaging and secretion in neurons. BDNF is synthesized as a pre-proBDNF protein, which has its pre-sequence cleaved off in the endoplasmic reticulum (ER). The resulting 32-kDa proBDNF moves, via the Golgi apparatus, into the trans-Golgi network (TGN) where two kinds of secretory vesicles are generated: those of the constitutive secretory pathway and those of the regulated pathway, whose secretion is activity-dependent. ProBDNF packaged in both types of vesicles is either proteolytically cleaved and secreted as 14-kDa mBDNF, or secreted as proBDNF and cleaved by extracellular proteases. The extent of the intra and extracellular processing of proBDNF is not exactly clear, but secretion of the proBDNF predominates. Both proBDNF and mBDNF are preferentially packaged into vesicles of the regulated secretory pathway. Once released, proBDNF binds preferentially to pan neurotrophin receptor p75^NTR and mBDNF binds preferentially to both pre-and post-synaptic TrkB receptors, activating different intracellular secondary messenger cascades and affecting distinct cellular responses.

Figure 3

BDNF–TrkB and BDNF–p75^NTR signalling pathways. BDNF binds TrkB with high affinity to induce its dimerization and autophosphorylation of tyrosine residues in the cytoplasmic kinase domain that serve as docking sites for effector molecules and trigger the activation of three main signalling pathways: PLCγ, PI3K and ERK cascades, which ultimately lead to the phosphorylation and activation of the transcription factor CREB that mediates transcription of genes essential for the survival and differentiation of neurons. The recruitment of PLCγ increases intracellular Ca²⁺ levels and leads to the activation of CaMKII to phosphorylate CREB. PI3K can be activated via the Shc/Grb2/SOS complex through Gab1 and by IRS1/2. Lipid products generated by the activated PI3K, the phosphatidylinositides, bind and activate protein kinase Akt, upstream of CREB. The ERK cascade can be activated both by the Shc/Grb2/SOS complex and by PI3K. ERK phosphorylation leads directly to CREB phosphorylation. Both Akt and ERK activate mTOR, responsible for enhanced translation initiation. BDNF binds p75^NTR with low affinity, leading to apoptosis through the JNK cascade or cell survival through the NF-kB cascade. PLCγ, phospholipase Cγ; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; CaMKII, calcium-calmodulin dependent kinase; Shc, src homology domain containing; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless; Gab1, Grb-associated binder 1; IRS1/2, insulin receptor substrates 1/2; CREB, cAMP-calcium response element binding protein; Ras, GTP binding protein; Raf, Ras associated factor; MEK, MAP/Erk kinase; mTOR, mammalian target of rapamycin; TRAF4/6, tumour necrosis factor receptor associated factor 4/6; RIP2, receptor interacting protein 2; JNK, c-Jun N-terminal kinase; NF-kB, nuclear factor k B.

Figure 4

BDNF/TrkB actions on ligand-gated, voltage-gated and second-messenger-gated ion channels, which mediate fast and slow synaptic transmission in neurons. BDNF is transported anterogradely and retrogradely and can activate TrkB receptors both pre- and postsynaptically. The association of BDNF with TrkB modulates or activates ion channels including Na⁺, Ca²⁺ and K⁺ channels, within a range of seconds to minutes, through intracellular signalling cascades. TRPC3 is a non-selective cation channel that needs to be phosphorylated by TrkB to open, via PLCγ, a process also acting in the range of minutes. BDNF enhances glutamatergic neurotransmission by increasing open probability of NMDA (by promoting its phosphorylation, via Fyn-dependent and Fyn-independent mechanisms) and by upregulating AMPA expression. ERK signalling is involved in both NMDA and AMPA gating. In the millisecond range, BDNF/TrkB can directly gate the Na_v1.9 Na⁺, the K_v1.3 K⁺ and the Kir3 K⁺ ion channels. The resulting depolarizations contribute to the facilitation of the induction of LTP.

Figure 5

Model proposed for the role of BDNF on excitatory and inhibitory circuits in the brain and its consequences on LTP and LTM. While a physiological amount of BDNF in the normal brain has been demonstrated to have positive effects on learning and memory, both an increased level of BDNF, and a decreased level of BDNF may disrupt the equilibrium between inhibitory and excitatory neurotransmission in the brain, leading to a loss of synaptic refinement and consequently impairing LTP, learning and memory.