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Prominent Postsynaptic and Dendritic Exocytosis of Endogenous BDNF Vesicles in BDNF-GFP Knock-in Mice

  • Julia Leschik
  • Robert Eckenstaler
  • Thomas Endres
  • Thomas Munsch
  • Elke Edelmann
  • Karin Richter
  • Oliver Kobler
  • Klaus-Dieter Fischer
  • Werner Zuschratter
  • Tanja Brigadski
  • Beat Lutz
  • Volkmar LessmannEmail author
Article
  • 277 Downloads

Abstract

Brain-derived neurotrophic factor (BDNF) is a secreted messenger molecule that is crucial for neuronal function and induction of synaptic plasticity. Although altered availability of BDNF underlies many neurological deficits and neurodegenerative disorders, secretion dynamics of endogenous BDNF are unexplored. We generated a BDNF-GFP knock-in (KiBE) mouse, in which GFP-labeled BDNF is expressed under the control of the unaltered endogenous mouse BDNF gene regulatory elements. This KiBE mouse model enables for the first time live cell imaging analysis of endogenous BDNF dynamics. We show that BDNF-GFP release and biological activity in vivo are unaffected by the GFP tag, since homozygous KiBE mice, which lack wild-type BDNF, are healthy and have a normal life expectancy. STED superresolution microscopy shows that 70% of BDNF-GFP vesicles in KiBE mouse neurites are localized in dendrites, being typically 200 nm away from synaptic release sites. Live cell imaging in hippocampal slices also reveals prominent targeting of endogenous BDNF-GFP vesicles to dendrites. Fusion pore opening and cargo release of dendritic BDNF vesicles start within 30 s after a strong depolarizing stimulus and continue for > 100 s thereafter, revealing an astonishingly delayed and prolonged release of endogenous BDNF.

Keywords

Neurotrophin BDNF Neuropeptide secretion Hippocampus Exocytosis Secretory granules GFP knock-in 

Notes

Acknowledgements

We would like to thank Dr. Kurt Gottmann for valuable suggestions and discussions, Sabine Eichler, Regina Ziegler, Margit Schmidt, Anja Reupsch, Danka Dormann, Andrea Conrad, Anisa Kosan, and Ruth Jelinek, for expert technical assistance, Yury Kovalchuk for valuable suggestions regarding the linear unmixing procedure, as well as Ralf Mohrmann for important comments on the manuscript.

Author Contributions

Experiments were performed by JL, RE, TB, TM, KR, EE. The data were analyzed by RE, JL, TE, TM, TB, EE, OK, WZ and VL. Experiments were designed by VL, BL, TB, JL. The study was designed and supervised by VL and BL. The manuscript was written by VL with the help of BL, JL, TB, TE, TM.

Funding

This work was funded by the German Research foundation (DFG SFB 779 and LE 1020/2-1 to VL, and LU 775/5-1 to BL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1551_MOESM1_ESM.pdf (2 mb)
Suppl. Fig. 1: Distribution of genotypes in litters from heterozygous KiBE breeding pairs and SC-CA1 LTP in 2–3 months old KiBE mice A) Distribution of genotypes in one month old animals across the whole KiBE stock, obtained from crossing heterozygous KiBE (KiBE+/-) males and females. Percentage of homozygous KiBE (KiBE+/+) animals was slightly smaller than expected from Mendelian distribution, indicating that some homozygous animals died until they reached one month of age. First digits indicate the number of animals, second digits indicate the percentage of this group in relation to the whole colony. B) For the experimental colony, we kept only those litters that contained at least one homozygous animal. Analysis of the proportion of the genotypes in this colony revealed a very stable distribution of the genotypes across all ages, which is interestingly close to the expected distribution according to the Mendelian law. Digits at the bottom of each column indicate the total number of animals analyzed in each age group. C) LTP elicited with 3x (interval 5 s) 30 pulses at 100 Hz (indicated by arrow at time point 0) was intact in homozygous (green) and heterozygous (blue) KiBE mice compared to respective WT littermates (red). Time course of LTP recordings is shown on the left, the bar chart on the right depicts mean fEPSP slopes 50–60 min after LTP induction. D) The BDNF dependency of the employed LTP induction protocol was verified in heterozygous BDNF knockout animals (BDNF+/-, black) and respective WT littermates (red). LTP was abolished in BDNF +/- mice. Data are represented as mean ± SEM. Numbers of recorded slices and animals are shown in the bars. The LTP protocol is shown as inset. (PDF 2039 kb)
12035_2019_1551_MOESM2_ESM.pdf (3.4 mb)
Suppl. Fig. 2: Anti-GFP immunohistochemical detection of BDNF-GFP in hippocampal CA1, CA3, and DG areas. (a-d) Anti-GFP immunofluorescent detection of BDNF-GFP in homozygous KiBE mouse hippocampal slices. Somato-dendritic staining of BDNF-GFP is most prominent in the CA3 layer (c; compare Fig.2). A similar incidence and intensity of somatic BDNF-GFP IHC signal is observed in DG granule cells (gc) and CA4 hilar mossy cells (b). A lower incidence of BDNF-GFP immunopositive cells with slightly lower intensity is also observed in CA1 pyramidal cells (a). (e, f) Development of anti-GFP immunohistochemical staining in homozygous KiBE mice with immunoperoxidase labeling followed by diaminobenzidine incubation. Note also here the strong labeling of CA3 pyramidal neuron somata and dendrites (middle), as well as the numerous CA1 pyramidal cell (left), granule cell (right), and hilar mossy cell somata (right), compared to wt littermate control (f). (PDF 3511 kb)
12035_2019_1551_MOESM3_ESM.pdf (1.6 mb)
Suppl. Fig. 3: Localization of BDNF-GFP vesicles in dendrites of hippocampal KiBE mouse neurons. Upper panel: Immunofluorescent detection (red) of anti-GFP staining in cultured hippocampal homozygous KiBE mouse neurons (14 DIV), compared to wt littermate control. The individual neurons in a-d were counterstained with antibodies as indicated, and white boxes are shown at higher magnification for different stainings in lower panels. BDNF-GFP: endogenous BDNF-GFP fluorescence (green). Anti-GFP: detection with an anti GFP antibody (red). MAP2: anti-MAP2 antibody staining (blue). Bassoon: anti-Bassoon immunodetection (blue). PSD95: anti-PSD95 antibody staining (blue). Lower panel: merged pictures of green, blue, and red fluorescence detected in the same fields of view. Note the exact colocalization of green GFP and red anti-GFP signals for all BDNF-GFP vesicles. BDNF GFP vesicles are most prominently detected in dendrites. Frequent localization of BDNF-GFP vesicles is observed at postsynaptic glutamatergic structures (as indicated by colocalization with PSD95), but in some cases also in Bassoon positive presynaptic structures. (PDF 1607 kb)
12035_2019_1551_MOESM4_ESM.pdf (1.3 mb)
Suppl. Fig. 4: Nearest neighbor analysis of BDNF-GFP vesicles to PSD95 and Bassoon in STED images (a) Pre- or postsynaptic structures (Bassoon, PSD95) grouped according to their nearest neighbor distance to the closest BDNF-GFP vesicle (40 nm binning). No obvious difference in distance distribution between pre- or postsynaptic structures could be observed. (b) Average distance of BDNF-GFP vesicles to closest Bassoon or PSD95 marker, respectively, within a perimeter of 100 nm around the synaptic structure showed no significant difference. (c) BDNF-GFP vesicles grouped according to their nearest neighbor distance to the closest synaptic structure (Bassoon, PSD95; 40 nm binning) showed a similar distribution. (d) Average distance of Bassoon or PSD95 to closest BDNF-GFP vesicle within a perimeter of 100 nm around the vesicle. Again no significant difference in distances was observed. (PDF 1363 kb)
12035_2019_1551_MOESM5_ESM.pdf (2.5 mb)
Suppl. Fig. 5: Basic vesicular properties in heterozygous and homozygous KiBE mice (a, b). Live cell imaging of BDNF-GFP vesicles in cultured hippocampal neurons from KiBE+/+ mice (a) and wt littermate controls (b) recorded at 14 DIV using epifluorescence microscopy. Left: Phase contrast images. Right: endogenous green (BDNF-GFP) fluorescence (shown in black and white). White boxed area is shown at higher magnification at indicated time points. Colored arrows depict single BDNF-GFP vesicles. Cells were continuously superfused with HEPES buffered saline (HBS: 20 mM HEPES, 100 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 1 mM Na2HPO4, 10 mM Glucose, 10 μM Glycine in H2O at pH = 7,39). Starting at 0 s cells were superfused with HBS supplemented with 5 mM NH4Cl to neutralize pH in BDNF-GFP vesicles, thereby unquenching GFP fluorescence. Note the increase in BDNF-GFP vesicle fluorescence in dendrites upon pH neutralization in (a) but not (b). (c) Plot of fluorescence intensities of vesicles marked by colored arrows in (a). (d) Average increase in fluorescence intensity of dendritic vesicles of 7 cells for each genotype. Dendritic branches as shown in (a) for ROIs in homozygous (n = 48) or heterozygous (n = 51) KiBE mouse cultures were analyzed. (e) Normalized average amplitude of fluorescence increase in response to NH4Cl (KiBE+/-: 2.47 ± 0.11; KiBE+/+: 2.46 ± 0.11; t-test: t = 0.02, p = 0.98). (f, g) Average absolute fluorescence intensity of BDNF-GFP vesicles in the absence (f) and the presence of NH4Cl (g), added to assure neutral pH in all vesicles recorded. Note the doubling of intravesicular fluorescence intensity in neurons from homozygous (n = 6 cells) compared to heterozygous (n = 7) KiBE mice (without NH4Cl: KiBE+/-: 94.8 ± 10.3 a.u.; KiBE+/+: 191.1 ± 12.3 a.u.; t-test:, t = 5.90, p = 0.0001; with NH4Cl: KiBE+/-: 209.2 ± 15.9 a.u.; KiBE+/+: 438.1 ± 38.3 a.u.; t-test: t = 5.160, p = 0.0003). (h, i) Apparent vesicle size (KiBE+/-: 0.40 ± 0.04 μm2; KiBE+/+: 0.42 ± 0.03 μm2; t-test: t = 0.34, p = 0.74) and vesicle density (KiBE+/-: 0.40 ± 0.03 per μm2; KiBE+/+: 0.45 ± 0.04 per μm2; t-test: t = 1.079, p = 0.30) were both indistinguishable between the two genotypes. In homozygous KiBE mice, dendrites contained 4.5 ± 0.4 vesicles per 10 μm dendritic length, whereas BDNF-GFP transfected wt mouse neurons harbored 5.2 ± 0.2 per 10 μm dendritic length. Identical illumination conditions and image exposure times were used for all 3 groups of neurons. (PDF 2594 kb)
12035_2019_1551_MOESM6_ESM.pdf (1.3 mb)
Suppl. Fig. 6: Relative fluorescence intensity of BDNF-GFP vesicles in KiBE mouse neurons versus WT neurons overexpressing BDNF-GFP. Normalized fluorescence intensity of BDNF-GFP vesicles in cultured hippocampal neurons from heterozygous and homozygous KiBE mice, respectively, vs. intensity of BDNF-GFP vesicles in wt mouse hippocampal neurons transfected with BDNF-GFP. Identical illumination conditions and image exposure times were used for all 3 groups of neurons. Note the roughly 30x and 60x lower BDNF-GFP fluorescence of vesicles in KiBE+/+ and KiBE+/- neurons, respectively, compared to BDNF-GFP overexpression. (PDF 1365 kb)
12035_2019_1551_MOESM7_ESM.avi (5.3 mb)
Suppl. movie 1: Fusion pore opening of BDNF-GFP vesicles in KiBE mouse neurons. Fusion pore opening (FPO) in a KiBE+/+ mouse hippocampal neuron at 17 DIV in response to elevated K+ (50 mM) induced depolarization. Under these conditions FPO is visible as a sudden increase in fluorescence intensity, due to unquenching of GFP fluorescence, followed by subsequent release of BDNF-GFP that is visible as decline in fluorescence intensity (compare Fig. 10). (AVI 5425 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Julia Leschik
    • 2
  • Robert Eckenstaler
    • 1
  • Thomas Endres
    • 1
  • Thomas Munsch
    • 1
    • 6
  • Elke Edelmann
    • 1
    • 6
  • Karin Richter
    • 4
  • Oliver Kobler
    • 3
  • Klaus-Dieter Fischer
    • 4
  • Werner Zuschratter
    • 3
  • Tanja Brigadski
    • 1
    • 7
  • Beat Lutz
    • 2
    • 5
  • Volkmar Lessmann
    • 1
    • 6
    Email author
  1. 1.Institute of PhysiologyMedical Faculty, Otto-von-Guericke UniversityMagdeburgGermany
  2. 2.Institute of Physiological ChemistryUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
  3. 3.Laboratory for Electron and Laserscan MicroscopyLeibniz Institute for NeurobiologyMagdeburgGermany
  4. 4.Institute of Biochemistry and Cell Biology, Medical FacultyOtto-von-Guericke-UniversityMagdeburgGermany
  5. 5.German Resilience CenterUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
  6. 6.Center for Behavioral Brain Sciences (CBBS)MagdeburgGermany
  7. 7.Department of Informatics and Microsystem TechnologyUniversity of Applied Sciences KaiserslauternZweibrueckenGermany

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