Brain-Derived Neurotrophic Factor Induces Long-Term Potentiation in Intact Adult Hippocampus: Requirement for ERK Activation Coupled to CREB and Upregulation ofArcSynthesis

Abstract

Brain-derived neurotrophic factor (BDNF) is implicated in longterm synaptic plasticity in the adult hippocampus, but the cellular mechanisms are little understood. Here we used intrahippocampal microinfusion of BDNF to trigger long-term potentiation (BDNF-LTP) at medial perforant path-granule cell synapses in vivo. BDNF infusion led to rapid phosphorylation of the mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated protein kinase) and p38 but not JNK (c-Jun N-terminal protein kinase). These effects were restricted to the infused dentate gyrus; no changes were observed in microdissected CA3 and CA1 regions. Local infusion of MEK (MAP kinase kinase) inhibitors (PD98059 and U0126) during BDNF delivery abolished BDNF-LTP and the associated ERK activation. Application of MEK inhibitor during established BDNF-LTP had no effect. Activation of MEK-ERK is therefore required for the induction, but not the maintenance, of BDNF-LTP. BDNF-LTP was further coupled to ERK-dependent phosphorylation of the transcription factor cAMP response element-binding protein. Finally, we investigated the expression of two immediate early genes, activity-regulated cytoskeleton-associated protein (Arc) and Zif268, both of which are required for generation of late, mRNA synthesis-dependent LTP. BDNF infusion resulted in selective upregulation of mRNA and protein for Arc. In situ hybridization showed that Arc transcripts are rapidly and extensively delivered to granule cell dendrites. U0126 blocked Arc upregulation in parallel with BDNF-LTP. The results support a model in which BDNF triggers long-lasting synaptic strengthening through MEK-ERK and selective induction of the dendritic mRNA species Arc.

BDNF-induced local protein synthesis and synaptic plasticity

“…Intrahippocampal infusion of BDNF resulted in the accumulation of Arc transcripts in dendrites and triggered long-term potentiation (BDNF-LTP) at medial perforant path-granule cell synapses in vivo (Messaoudi et al, 2007;Ying et al, 2002), and similar effects were observed in cultured cerebrocortical neurons (Rao et al, 2006), but the mechanisms involved have not been clarified. BDNF signaling induces the phosphorylation of ZBP1 and local synthesis of b-actin in growth cones, contributing to growth cone turning (Sasaki et al, 2010).…”

Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats

“…Fos and Zif/268 are nuclear transcription factors that regulate the expression of late-target genes whereas the protein products of the effector genes, arc and bdnf, are rapidly expressed and delivered to activated synapses (Link et al 1995;Steward and Worley 2001;Ying et al 2002;Bozon et al 2003;Tongiorgi et al 2004). In addition, early phases of instrumental learning (Hernandez et al 2006;Kelly and Deadwyler 2003) elicit widespread zif/268 and arc induction throughout an extensive corticostriatal network in rats, whereas manipulation of BDNF levels in the brain alters cocaine-seeking in a regionally selective manner (Horger et al 1999;Lu et al 2004;Berglind et al 2007;Graham et al 2007).…”

“…BDNF promotes synaptic plasticity and synaptic consolidation that are dependent upon the transcription and translation of arc (Kang and Schuman 1996;Guzowski et al 2001;Messaoudi et al 2002;Bramham and Messaoudi 2005;Soule et al 2006;Wibrand et al 2006). Thus, an increase in bdnf mRNA in the cortex may drive the arc response by initiating translation of newly synthesized arc mRNA in activated dendritic spines (Yin et al 2002;Ying et al 2002). In addition, BDNFinduced arc synthesis during extinction learning may help drive synaptic consolidation to completion (Bramham and Messaoudi 2005;Haubensak et al 1998;Lessmann 1998), a mechanism likely necessary to consolidate learned associations into long-term memory.…”

The exclusive induction of extinction is gated by BDNF

“…Contrarily, the expression of BDNF IX is specifically increased following short durations of CS exposure, similar to the refractory changes in the Arc levels in CA1 (see above), a BDNF-regulated protein (Waltereit et al 2001;Yin et al 2002;Ying et al 2002), with prolonged CS exposures. The differential regulation of BDNF IX and Zif268 expression in the CA1 provides a conceptual framework for the role for the interaction of BDNF and Zif268 activities in the hippocampus in controlling the extinction of CFM, not only under conditions of recall that favor extinction, but under all situations following the retrieval of a nonreinforced CS.…”