PDF《Neuropharmacology》

Invited review BDNF mechanisms in late LTP formation: A synthesis and breakdown Debabrata Panja a,b , Clive R.

Bramham a,b,* a Department of Biomedicine, University of Bergen, Jonas Lies vei 91,

5009 Bergen, Norway b KG Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Jonas Lies vei 91,

5009 Bergen, Norway a r t i c l e i n f o Article history: Received

29 May

2013 Received in revised form

21 June

2013 Accepted

23 June

2013 Keywords: Brain-derived neurotrophic factor (BDNF) TrkB signaling Synaptic plasticity Long-term potentiation (LTP) Protein synthesis Translation control Cytoskeletal dynamics a b s t r a c t Unraveling the molecular mechanisms governing long-term synaptic plasticity is a key to understanding how the brain stores information in neural circuits and adapts to a changing environment. Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of stable, late phase long-term potentiation (L- LTP) at excitatory glutamatergic synapses in the adult brain. However, the mechanisms by which BDNF triggers L-LTP are controversial. Here, we distill and discuss the latest advances along three main lines: 1) TrkB receptor-coupled translational control underlying dendritic protein synthesis and L-LTP, 2) Mech- anisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-TrkB regulation of actin cytoskeletal dynamics in dendritic spines. Finally, we explore the inter-relationships between BDNF-regulated mechanisms, how these mechanisms contribute to different forms of L-LTP in the hippocampus and dentate gyrus, and outline outstanding issues for future research. This article is part of the Special Issue entitled '

BDNF Regulation of Synaptic Structure, Function, and Plasticity'

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2013 Elsevier Ltd. All rights reserved. 1. Introduction The compartmentalization of electrical and biochemical signals in dendritic spines makes glutamatergic synapses a natural locus for encoding information in neural networks. Hence, activity- dependent forms of synaptic plasticity, such as long-term poten- tiation (LTP), long-term depression (LTD), and homeostatic plas- ticity (scaling), are of immense interest for elucidating the molecular mechanisms of memory formation, storage, and forget- ting. Stable, late phase LTP (L-LTP) is associated with enlargement and remodeling of the postsynaptic density (PSD), enlargement of pre-existing dendritic spines, as well as de novo synapse formation (Lisman and Raghavachari, 2006;

Bourne and Harris, 2008). Such large-scale growth and remodeling is thought to require de novo synthesis of synaptic proteins, along with protein traf?cking and degradation. The secretory peptide, brain-derived neurotrophic factor (BDNF), plays a critical role in stimulating the formation of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms by which BDNF promotes L-LTP have not been established for any speci?c brain region. Gluta- matergic synapses are capable of expressing mechanistically distinct forms of LTP, and glutamatergic synapses differ in morphology, physiology, and molecular composition between brain regions and between synapses on the same neuron. With a focus on how BDNF signaling controls L-LTP, we distill and discuss the latest advances along three main lines: 1) tropomyosin-like kinase B (TrkB) receptor-coupled translational control underlying local protein synthesis and L-LTP, 2) mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF- Abbreviations: Arc, activity-regulated cytoskeleton-associated protein;