BDNF regulation of synaptic structure, function, and plasticity

Abstract

Brain-derivedneurotrophic factor(BDNF)works in multifacetedways to shape the structure and function of neural circuits acrossthe lifespan. Perturbations in BDNF systems are implicated inmany neurological and neuropsychiatric conditions. Perhapsreflecting the unexpected diversity in BDNF functions, the biologyof BDNF is currently at the center of debate in many areas of basicand clinical neuroscience. The reviews in this Special Issue presentand discuss the latest advances on BDNF regulation of synapticstructure, function, and plasticity and its implications for brain dis-orders. The fresh and critical insights provided in this volume have,webelieve,succeededindistilling thestate-of-the-artinawaythatwill help to set the agenda for future research.DeinhardtandChao(D-13-00213R1)describethecellularmech-anisms by which mature BDNF and its precursor, proBDNF, shapeneuronalmorphologyandsynapseformation.Thearticlehighlightsthe coordinate, and often opposing, actions of BDNF and proBDNFon both local and long-range (retrograde axonal) signaling. Edel-mann and colleagues (D-13-00233R1) discuss current knowledgeof BDNF secretion from pre- and postsynaptic sites and the mech-anisms of BDNF action in different forms of LTP, with emphasison spike-timing-dependent LTP and mossy fiber LTP. Zagrebelskyand Korte (D-13-00198R1) discuss the pre- and postsynaptic ac-tions of BDNF on excitatory and inhibitory neurons, debate thecontribution of permissive and instructive roles of BDNF in LTPand LTD, and contrast the effects of exogenous and endogenousBDNF in modulating neuronal morphology and synapse formation.BDNF regulation of protein synthesis is the focus of three re-views. Leal and colleagues (D-13-00106R1) discuss how BDNF al-ters the synaptic proteome through effects on mRNA transport,storage, and translation in dendrites, and likely impacts transla-tional capacity as well as synaptic function. Ruiz and colleagues(D-13-00002R1) elaborate on microRNA function in BDNFsignaling, with emphasis on how BDNF regulation of miRNA pro-cessing leads to enhanced translation of a specific set ofmicroRNA-targeted mRNAs. Panja and Bramham (D-13-00499R1)consider the role of BDNF signaling in driving protein synthesis-dependent LTP, the emerging relationship between actin cytoskel-etal regulation and translation in dendritic spines, and the mecha-nisms by which exogenous BDNF rescues LTP in the absence ofprotein synthesis.Extending from synaptic plasticity to memory, Bekinschteinand colleagues (D-13-00069R1) review BDNF function in the for-mation and long-term persistence of memory, and the regulationof BDNF transcription during memory processing by dopamineand serotonin. Ipe Ninan (D-13-00232R1) discusses how changesin synaptic BDNF signaling, either in response to stress or as aresult of mutations in the BDNF gene, alter medial prefrontalcortex-hippocampal-amygdala circuits involved in fear learningand extinction of aversive memories. Ninan also considers howsuch changes impact the development of affective disorders.Scharfman and Maclusky (D-13-00007R1) review the effects of es-trogen and testosterone on BDNF expression in the hippocampalmossy fiber pathway, and consider how gender differences inmossy fiber-CA3 function may contribute to the higher incidenceof anxiety-related disorders and post-traumatic stress syndromein women relative to men. Nina Karpova (D-13-00003R1) summa-rizes recent findings on the long-term epigenetic programming ofBDNF gene expression through DNA methylation, histone modifi-cation, and microRNAs, and discusses how the epigenetic state ofthe BDNF gene could predispose to mood disorders as well asnon-responsiveness of mood disorders to current treatmentstrategies.Singer and colleagues (D-13-00262R1) review the mechanismsby which BDNF drives the refinement of auditory circuits fromthe onset of sensory experience into adulthood, and discuss theimpact of acoustically-induced sensory trauma on these systems.The last two articles deal with specific neurodevelopmentaldisorders. Fragile X syndrome (FXS) is the leading cause ofinherited intellectual disability. Castren and Castren (D-13-00205R1) review how loss of Fragile X protein perturbs plasticityand circuit function in the adult brain. The authors emphasizethe role of neuronal progenitor differentiation and early develop-mental defects in BDNF signaling in the pathophysiology of FXS.Rett syndrome, the leading cause of intellectual disability inwomen, is thought to involve mutation in MeCP2 and consequentderegulation of BDNF transcription. Wei and Pozzo-Miller (D-13-00080R1) detail the mechanisms by which MeCP2 both activatesand represses BDNF transcription, and may dynamically switch be-tween these states in the “dual operation model”. The authors alsodiscuss how novel strategies for improving BDNF signaling inMecp2 knockout mice may instruct therapeutic strategies for Rettsyndrome.Clive R. Bramham