Localization of Brain-Derived Neurotrophic Factor to Distinct Terminals of Mossy Fiber Axons Implies Regulation of Both Excitation and Feedforward Inhibition of CA3 Pyramidal Cells

Danzer, Steve C.; McNamara, James O

doi:10.1523/jneurosci.3846-04.2004

Cited by 84 publications

(79 citation statements)

References 66 publications

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“…BDNF is the primary ligand for TrkB activation in the brain, which is most enriched in the axonal terminals of the hippocampal MFs (19). Although TrkB activation can be achieved by other nonneurotrophin-based mechanisms, such as Zinc-mediated and Srcdependent transactivation of TrkB (30), the potency for BDNF to activate TrkB is higher by hundreds of fold (30).…”

Section: Discussionmentioning

confidence: 99%

“…4B). The BDNF protein synthesized in DG is transported and stored at high concentrations in the hippocampal mossy fiber (MF) axonal terminals that form synapses with CA3 pyramidal neurons (19). Seizure-induced neuronal activation releases BDNF from the MF synapses, which leads to robust activation of TrkB in the MF tract (19,20).…”

Section: Activity-dependent Translation Of Bdnf Mediated By the Long mentioning

confidence: 99%

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Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF)

Lau¹,

Irier²,

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

203

186

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Expression of the brain-derived neurotrophic factor (BDNF) is under tight regulation to accommodate its intricate roles in controlling brain function. Transcription of BDNF initiates from multiple promoters in response to distinct stimulation cues. However, regardless which promoter is used, all BDNF transcripts are processed at two alternative polyadenylation sites, generating two pools of mRNAs that carry either a long or a short 3′UTR, both encoding the same BDNF protein. Whether and how the two distinct 3′UTRs may differentially regulate BDNF translation in response to neuronal activity changes is an intriguing and challenging question. We report here that the long BDNF 3′UTR is a bona fide cis-acting translation suppressor at rest whereas the short 3′UTR mediates active translation to maintain basal levels of BDNF protein production. Upon neuronal activation, the long BDNF 3′UTR, but not the short 3′UTR, imparts rapid and robust activation of translation from a reporter. Importantly, the endogenous long 3′UTR BDNF mRNA specifically undergoes markedly enhanced polyribosome association in the hippocampus in response to pilocarpine induced-seizure before transcriptional up-regulation of BDNF. Furthermore, BDNF protein level is quickly increased in the hippocampus upon seizure-induced neuronal activation, accompanied by a robust activation of the tropomyosin-related receptor tyrosine kinase B. These observations reveal a mechanism for activity-dependent control of BDNF translation and tropomyosin-related receptor tyrosine kinase B signaling in brain neurons.alternative 3′UTR | tropomyosin-related kinase receptor B | hippocampal mossy fiber | epilepsy B rain-derived neurotrophic factor (BDNF) is known to elicit a plethora of functions in the brain via activation of the tropomyosin-related receptor tyrosine kinase B (TrkB), ranging from neuronal survival and differentiation to circuit development and synaptic plasticity (1-3). Abnormalities in BDNF function have been implicated in both neurological and psychiatric disorders (4-6). To accommodate such diverse functions, a variety of mechanisms have evolved that tightly control BDNF expression. Transcription of the BDNF gene can be initiated from nine distinct promoters in mammals, allowing for sophisticated regulation by divergent extracellular and developmental cues (7-9). Moreover, the primary BDNF transcript can be processed at two alternative polyadenylation sites in all tissues examined, giving rise to two pools of BDNF mRNAs that harbor either a short or a long 3′UTR of 0.35 kb and 2.85 kb in length, respectively (8, 9). Each BDNF mRNA isoform encodes for the same BDNF protein. However, the relative abundance of the short and long 3′UTR BDNF mRNAs differ in various brain regions (10). The different 3′UTRs in BDNF mRNAs presumably interact with distinct trans-acting factors, thus offering a mechanism to increase the capacity and complexity for regulation of BDNF expression at posttranscriptional levels, such as translation and subcellular localization, which ...

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Section: Discussionmentioning

confidence: 99%

Section: Activity-dependent Translation Of Bdnf Mediated By the Long mentioning

confidence: 99%

Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF)

Lau¹,

Irier²,

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

203

186

View full text Add to dashboard Cite

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“…The present study uses the Thy1-GFP mouse line to characterize granule cell morphology after the development of epilepsy (Feng et al, 2000;Danzer and McNamara, 2004). In this mouse line, granule cells do not express GFP until they are ϳ4 weeks old.…”

Section: Gfp Is Expressed In Mature Granule Cells In the Thy1-gfp Moumentioning

confidence: 99%

Pilocarpine-Induced Seizures Cause Selective Time-Dependent Changes to Adult-Generated Hippocampal Dentate Granule Cells

Walter¹,

Murphy²,

Pun³

et al. 2007

J. Neurosci.

Self Cite

163

176

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Aberrantly interconnected granule cells are characteristic of temporal lobe epilepsy. By reducing network stability, these abnormal neurons may contribute directly to disease development. Only subsets of granule cells, however, exhibit abnormalities. Why this is the case is not known. Ongoing neurogenesis in the adult hippocampus may provide an explanation. Newly generated granule cells may be uniquely vulnerable to environmental disruptions relative to their mature neighbors. Here, we determine whether there is a critical period after neuronal birth during which neuronal integration can be disrupted by an epileptogenic insult. By bromodeoxyuridine birthdating cells in green fluorescent protein-expressing transgenic mice, we were able to noninvasively label granule cells born 8 weeks before (mature), 1 week before (immature), or 3 weeks after (newborn) pilocarpineepileptogenesis. Neuronal morphology was examined 4 and 8 weeks after pilocarpine treatment. Strikingly, almost 50% of immature granule cells exposed to pilocarpine-epileptogenesis exhibited aberrant hilar basal dendrites. In contrast, only 9% of mature granule cells exposed to the identical insult possessed basal dendrites. Moreover, newborn cells were even more severely impacted than immature cells, with 40% exhibiting basal dendrites and an additional 20% exhibiting migration defects. In comparison, Ͻ5% of neurons from normal animals exhibited either abnormality, regardless of age. Together, these data demonstrate the existence of a critical period after the birth of adult-generated neurons during which they are vulnerable to being recruited into epileptogenic neuronal circuits. Pathological brain states therefore may pose a significant hurdle for the appropriate integration of newly born endogenous, and exogenous, neurons.

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“…To minimize the mortality rate of the procedure, animals were allowed to remain in SE for 3 hr rats by administering diazepam (10 mg/kg, i.p.) to quell behavioral seizures (Danzer and McNamara, 2004;Mello et al, 1993;Pacheco Otalora et al, 2006). All animals that received pilocarpine were given Nutra-Gel ® soft food (Bio-Serv, Frenchtown, NJ), fresh apples and water in an easily-reachable container inside the recovery cage for 48 hr after SE induction.…”

Section: Experimental Procedures Animals and Rat Model Of Chronic Epilmentioning

confidence: 99%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

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Localization of Brain-Derived Neurotrophic Factor to Distinct Terminals of Mossy Fiber Axons Implies Regulation of Both Excitation and Feedforward Inhibition of CA3 Pyramidal Cells

Cited by 84 publications

References 66 publications

Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF)

Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF)

Pilocarpine-Induced Seizures Cause Selective Time-Dependent Changes to Adult-Generated Hippocampal Dentate Granule Cells

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

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