Depletion of putative chemosensitive respiratory neurons in the ventral medullary surface in multiple system atrophy

Brain. 2007 Feb;130(Pt 2):469-75. doi: 10.1093/brain/awl357.

Abstract

Multiple system atrophy (MSA) is a disorder that may manifest with reduced respiratory chemosensitivity and central sleep apnoea. Chemosensitive glutamatergic and serotonergic neurons located just beneath the ventral medullary surface, corresponding to the human arcuate nucleus (ArcN), have recently been implicated in control of automatic breathing in response to hypercapnia and hypoxia. We sought to determine whether these neurons were affected in MSA. Medullae were obtained at post-mortem from 11 patients (8 men, 3 women, age 64 +/- 3 years) with neuropathologically confirmed MSA and 11 control subjects (6 men and 5 women, age 66 +/- 4 years). Fifty micrometre sections obtained throughout the medulla were processed for vesicular glutamate transporter-2 (VGLUT-2), tryptophan-hydroxylase (TrOH), glial fibrillary acid protein (GFAP) and alpha-synuclein immunoreactivity. Cell counts, GFAP immunoreactivity and presence of glial cytoplasmic inclusions (GCIs) were assessed in the ArcN. In MSA, compared with controls, there was a marked depletion of ArcN neurons immunoreactive for either VGLUT-2 (74 +/- 21 versus 342 +/- 84 cells/section, P < 0.004) or TrOH (5 +/- 1 versus 16 +/- 2 cells/section, P < 0.001). There was also marked astrocytic gliosis and accumulation of alpha-synuclein immunoreactive GCIs in the ventral medullary surface in all cases. Our results indicate that there is severe loss of putative chemosensitive glutamatergic and serotonergic neurons as well as marked astrocytic gliosis in the ventral medullary surface in MSA. This may provide a possible morphological basis for impaired respiratory chemosensitivity and central sleep apnoea in this disorder.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Arcuate Nucleus of Hypothalamus / pathology
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Gliosis / etiology
  • Gliosis / metabolism
  • Gliosis / pathology
  • Humans
  • Male
  • Medulla Oblongata / metabolism
  • Medulla Oblongata / pathology*
  • Middle Aged
  • Multiple System Atrophy / complications
  • Multiple System Atrophy / metabolism
  • Multiple System Atrophy / pathology*
  • Multiple System Atrophy / physiopathology
  • Neurons / metabolism
  • Neurons / pathology*
  • Respiratory Mechanics*
  • Sleep Apnea, Obstructive / etiology
  • Sleep Apnea, Obstructive / metabolism
  • Sleep Apnea, Obstructive / pathology
  • Tryptophan Hydroxylase / metabolism
  • Vesicular Glutamate Transport Protein 2 / metabolism
  • alpha-Synuclein / metabolism

Substances

  • Glial Fibrillary Acidic Protein
  • SLC17A6 protein, human
  • Vesicular Glutamate Transport Protein 2
  • alpha-Synuclein
  • Tryptophan Hydroxylase