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PMID:20089890

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Citation

Newell-Litwa, K, Chintala, S, Jenkins, S, Pare, JF, McGaha, L, Smith, Y and Faundez, V (2010) Hermansky-Pudlak protein complexes, AP-3 and BLOC-1, differentially regulate presynaptic composition in the striatum and hippocampus. J. Neurosci. 30:820-31

Abstract

Endosomal sorting mechanisms mediated by AP-3 and BLOC-1 are perturbed in Hermansky-Pudlak Syndrome, a human genetic condition characterized by albinism and prolonged bleeding (OMIM #203300). Additionally, mouse models defective in either one of these complexes possess defective synaptic vesicle biogenesis (Newell-Litwa et al., 2009). These synaptic vesicle phenotypes were presumed uniform throughout the brain. However, here we report that AP-3 and BLOC-1 differentially regulate the composition of presynaptic terminals in the striatum and dentate gyrus of the hippocampus. Quantitative immunoelectron microscopy demonstrated that the majority of AP-3 immunoreactivity in both wild-type striatum and hippocampus localizes to presynaptic axonal compartments, where it regulates synaptic vesicle size. In the striatum, loss of AP-3 (Ap3d(mh/mh)) resulted in decreased synaptic vesicle size. In contrast, loss of AP-3 in the dentate gyrus increased synaptic vesicle size, thus suggesting anatomically specific AP-3-regulatory mechanisms. Loss-of-function alleles of BLOC-1, Pldn(pa/pa), and Muted(mu/mu) revealed that this complex acts as a brain-region-specific regulator of AP-3. In fact, BLOC-1 deficiencies selectively reduced AP-3 and AP-3 cargo immunoreactivity in presynaptic compartments within the dentate gyrus both at the light and/or electron microscopy level. However, the striatum did not exhibit these BLOC-1-null phenotypes. Our results demonstrate that distinct brain regions differentially regulate AP-3-dependent synaptic vesicle biogenesis. We propose that anatomically restricted mechanisms within the brain diversify the biogenesis and composition of synaptic vesicles.

Links

PubMed PMC2824551 Online version:10.1523/JNEUROSCI.3400-09.2010

Keywords

Adaptor Protein Complex 3; Adaptor Protein Complex beta Subunits; Animals; Carrier Proteins/metabolism; Corpus Striatum/cytology; Corpus Striatum/metabolism; Embryo, Mammalian; Gene Expression Regulation/genetics; Hippocampus/cytology; Hippocampus/metabolism; Lectins/deficiency; Lectins/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Immunoelectron/methods; Neurons/cytology; Neurons/metabolism; Presynaptic Terminals/metabolism; Presynaptic Terminals/ultrastructure; R-SNARE Proteins/metabolism; Rats; Rats, Sprague-Dawley; Synaptic Vesicles/metabolism; Synaptic Vesicles/ultrastructure; Synaptophysin/metabolism; Synaptosomes/metabolism; Synaptosomes/ultrastructure; Transcription Factors/deficiency; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:AP3D1

part_of

GO:0030424: axon

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:19037)|part_of:(EMAPA:17549)

Seeded From UniProt

complete

MOUSE:AP3D1

part_of

GO:0043195: terminal bouton

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17549)|part_of:(EMAPA:19037)

Seeded From UniProt

complete

MOUSE:AP3D1

part_of

GO:0098794: postsynapse

ECO:0006003: electron microscopy evidence used in manual assertion

C

  • part_of:(UBERON:0002435)

Seeded From UniProt

complete

MOUSE:AP3D1

part_of

GO:0098793: presynapse

ECO:0005589: confocal microscopy evidence used in manual assertion

C

  • part_of:(UBERON:0002435)

Seeded From UniProt

complete

MOUSE:AP3D1

part_of

GO:0098793: presynapse

ECO:0005589: confocal microscopy evidence used in manual assertion

C

  • part_of:(UBERON:0002421)

Seeded From UniProt

complete

MOUSE:AP3D1

part_of

GO:0098793: presynapse

ECO:0006003: electron microscopy evidence used in manual assertion

C

  • part_of:(UBERON:0002435)

Seeded From UniProt

complete

MOUSE:AP3D1

part_of

GO:0098793: presynapse

ECO:0006003: electron microscopy evidence used in manual assertion

C

  • part_of:(UBERON:0002421)

Seeded From UniProt

complete


See also

References

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