ReviewRegulation of hippocampal synaptic plasticity by BDNF
Introduction
Synaptic plasticity describes the process by which synapses change in strength depending on the pattern of neuronal activity. These functional changes at the synapse, with an increase or decrease in synaptic efficacy, are accompanied by structural changes. Plasticity at excitatory synapses can be mediated at the presynaptic level, by changing the release of neurotransmitter molecules, or postsynaptically by changing the number, type, or properties of neurotransmitter receptors and their coupling to the intracellular signaling machinery.
Long-term potentiation (LTP) is an activity-induced long-lasting increase in the excitatory synaptic strength and, since its discovery, it has been identified as the prime candidate to be the cellular correlate of learning and memory (Lynch, 2004, Malenka, 2003b). Most of the research in this field has focused on the hippocampus, especially at the synapses between the presynaptic Schaffer collaterals and the postsynaptic CA1 pyramidal cells. Hippocampal LTP is typically divided into at least three distinct and sequential phases: short-term potentiation, early LTP (E-LTP), and late LTP (L-LTP). Short-term potentiation and E-LTP are transient and involve the modification of preexisting proteins, whereas L-LTP requires changes in gene expression and de novo protein synthesis, and lasts for hours or even days (Abraham, 2003, Kandel, 2001, Sweatt, 1999). It is now firmly established that neurotrophins, a small family of secreted proteins, are potent regulators of this form of synaptic plasticity. The neurotrophin family comprises the nerve growth factor (NGF) (Cohen et al., 1954), brain-derived neurotrophic factor (BDNF) (Barde et al., 1982), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5) (Lewin and Barde, 1996).
The physiological responses to neurotrophins are mediated by the activation of two distinct classes of membrane-bound receptors: the p75NTR interact with all neurotrophins in their precursor and mature forms, and the mature neurotrophins also interact in a differential manner with the tropomyosin-related kinase (Trk) receptors. NGF binds to TrkA, BDNF and NT4/5 bind to TrkB and NT3 binds to TrkC (Chao, 2003, Reichardt, 2006). A major advance in our understanding of neurotrophin physiology came when it was suggested that some of the neurotrophins can be released in response to neuronal activity (Thoenen, 1991). This observation encouraged additional studies that focused on the role of neurotrophins, in particular of BDNF, in activity-dependent forms of synaptic plasticity. BDNF stands out among all neurotrophins for its high and wide expression in the mammalian brain, in addition to its potent effects at many synapses. Furthermore, several aspects of the biology of this neurotrophin, including the release of BDNF, are regulated by neuronal activity.
BDNF has emerged as a key molecule involved in the control of neuronal differentiation and survival, synapse formation, and in the regulation of activity-dependent changes in synapse structure and function (Park and Poo, 2013). The available evidence indicates that BDNF is a major regulator of LTP in the hippocampus, and in other brain regions (Bramham and Messaoudi, 2005, Edelmann et al., 2014, Lu et al., 2008, Minichiello, 2009). In this review we will provide a critical insight into the role of BDNF in the regulation of hippocampal LTP and highlight the most prominent questions in the field that remain to be addressed.
Section snippets
Transcriptional and post-transcriptional regulation of Bdnf
The Bdnf gene is very complex, containing at least nine promoters (Aid et al., 2007), each driving the transcription of BDNF mRNAs carrying one of the alternative 5′ non-coding exons spliced to the common 3′ coding exon (Aid et al., 2007). Among these, promoter IV is highly responsive to neuronal activity, which is coupled to transient increases in the [Ca2+]i. Ca2+ influx through voltage-gated calcium channels (VGCC) and N-methyl-d-aspartate (NMDA) receptors (NMDAR) triggers Bdnf transcription
BDNF and long-term potentiation (LTP)
There are several different forms of LTP in the hippocampus; their properties and nature differ according to the hippocampal subregion and the induction protocol used. Most of these forms of LTP are associative, indicating that a weak input can be potentiated when associated with a strong convergent input, require NMDAR activation and have a postsynaptic component for its expression (Bliss and Collingridge, 1993, Bramham and Messaoudi, 2005). However, LTP at mossy fibers (MF) synapses (MF-CA3)
Effect of BDNF on protein synthesis
It is well established that protein synthesis is required for BDNF-dependent LTP in the hippocampus ((Kang and Schuman, 1996); for a review see Leal et al. (2014), Santos et al. (2010)). In fact, the effects of BDNF on L-LTP have been largely assigned to the effects of the neurotrophin on local protein synthesis at the synapse based on the transcripts locally available. The initial translation-dependent effects of BDNF are mediated by local activation of the translation machinery, while at
Balance between protein synthesis and protein degradation in BDNF-induced synaptic plasticity
The studies to evaluate the effects of BDNF on the proteome of cultured hippocampal (Manadas et al., 2009) and cerebrocortical (Liao et al., 2007) neurons showed an upregulation of several proteins and decrease in the expression of several others. These results suggest that BDNF may also affect the machinery involved in the degradation of proteins in the cell. Accordingly, BDNF was recently shown to increase calpain-2 activity at dendritic spines (Zadran et al., 2010), and the resulting
Concluding remarks and future perspectives
Despite the progress in our knowledge of the biology of BDNF and the role of the neurotrophin in activity-dependent changes in synapse structure and function, many key issues such as the spatiotemporal resolution of endogenous BDNF secretion and the exact sites where the neurotrophin exerts its effects are still poorly understood, especially in the adult hippocampus. Understanding these mechanisms is important since BDNF-mediated actions are very diverse and range in a time scale from
Acknowledgments
The work in the authors laboratory was supported by FEDER (QREN) through Programa Mais Centro, under projects CENTRO-07-ST24-FEDER-002002, CENTRO-07-ST24-FEDER-002006 and CENTRO-07-ST24-FEDER-002008, through Programa Operacional Factores de Competitividade—COMPETE and National funds via FCT—Fundação para a Ciência e a Tecnologia under projects Pest-C/SAU/LA0001/2013-2014, PTDC/SAU-NEU/104297/2008 and PEst-C/SAU/LA0001/2013-2014.
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These authors contributed equally to the present work.