The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes

Abstract

Protein synthesis in neurons is essential for the consolidation of memory and for the stabilization of activity-dependent forms of synaptic plasticity such as long-term potentiation (LTP). Activitydependent translation of dendritically localized mRNAs has been proposed to be a critical source of new proteins necessary for synaptic change. mRNA for the activity-regulated cytoskeletal protein, Arc, is transcribed during LTP and learning, and disruption of its translation gives rise to deficits in both. We have found that selective translation of Arc in a synaptoneurosomal preparation is induced by the brain-derived neurotrophic factor, a neurotrophin that is released during high-frequency stimulation patterns used to elicit LTP. This effect involves signaling through the TrkB receptor and is blocked by the N-methyl-D-aspartate-type glutamate receptor antagonist, MK801. The results suggest there is a synergy between neurotrophic and ionotropic mechanisms that may influence the specificity and duration of changes in synaptic efficacy at glutamatergic synapses.T he brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF) superfamily of neurotrophins (1, 2), influences the differentiation and survival of neurons and the maintenance of their arborizations (3-6). Other data suggest that BDNF is also involved in both short-and long-term plasticity of glutamatergic synapses (7,8). BDNF signaling enhances synaptic maturation and increases synaptic density in the hippocampus (9), and in the adult the synthesis and secretion of BDNF continue to be regulated by activity (10-12). Exogenous application of BDNF induces a rapid and persistent enhancement of synaptic transmission in hippocampal and cortical preparations (13,14) and facilitates the induction of long-term potentiation (LTP) in slices from young animals (15). Stimulation patterns used to elicit LTP also result in release of the BDNF protein from presynaptic terminals (16,17).Local protein synthesis may influence changes in synaptic efficacy induced by BDNF. Early and reversible effects of BDNF involve pre-and postsynaptic changes that do not require protein synthesis. For example, application of BDNF enhances evoked glutamate release (18) and increases the probability that the N-methyl-D-aspartate (NMDA) receptor channel will be open (19). Longer-term influences on synaptic efficacy, however, may require BDNF-induced local protein synthesis. BDNF-induced synaptic potentiation in hippocampal slices is blocked by inhibitors of protein synthesis (20). Potentiation induced by BDNF can be obtained in slices in which synapses have been severed from cell bodies, suggesting that synthesis of the required protein(s) is dendritically localized (20). In accord with this possibility, it has been shown that BDNF specifically induces the expression of transfected c-myc in dissected dendrites (21), and the dendritic synthesis of a reporter protein construct flanked by the 5Ј and 3Ј untranslated regions of ␣-calmodulin-dependent protein kinase II ]. These ...

Brain-Derived Neurotrophic Factor Triggers Transcription-Dependent, Late Phase Long-Term PotentiationIn Vivo

“…In this context, it should be pointed out that activation of the translation machinery in dendrites may go hand in hand with the arrival of Arc transcripts, effectively driving Arc protein synthesis at synaptic sites (Ying et al, 2002). Supporting this view, BDNF has been shown recently to stimulate posttranscriptional synthesis of Arc in isolated synaptoneurosomes (Yin et al, 2002). This mechanism may well be accentuated in the context of elevated Arc mRNA.…”

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

“…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.…”

BDNF-induced local protein synthesis and synaptic plasticity

“…The dendritic localization and translation of the Arc mRNA has been extensively studied (Messaoudi et al, 2007;Rao et al, 2006;Steward et al, 1998;Steward and Worley, 2001;Yin et al, 2002;Ying et al, 2002), and BDNF was shown to increase dendritic Arc mRNA and protein levels in cultured cortical neurons (Rao et al, 2006). A role for Arc in LTP was shown in experiments with intrahippocampal infusion of antisense (AS) oligodeoxynucleotides to inhibit Arc protein expression, which impaired the maintenance phase of LTP without affecting its induction (Guzowski et al, 2000).…”