Hermansky-Pudlak protein complexes, AP-3 and BLOC-1, differentially regulate presynaptic composition in the striatum and hippocampus

J Neurosci. 2010 Jan 20;30(3):820-31. doi: 10.1523/JNEUROSCI.3400-09.2010.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Intracellular Signaling Peptides and Proteins
  • 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*

Substances

  • Adaptor Protein Complex 3
  • Adaptor Protein Complex beta Subunits
  • Ap3d1 protein, mouse
  • Bloc1s6 protein, mouse
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lectins
  • R-SNARE Proteins
  • Synaptophysin
  • Transcription Factors