Location and connectivity determine GABAergic interneuron survival in the brains of South Hampshire sheep with CLN6 neuronal ceroid lipofuscinosis

Manfred J. Oswald, David N. Palmer, Graham W. Kay, Karen J. Barwell, Jonathan D. Cooper

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited neurodegenerative diseases. Sheep affected with the CLN6 form provide a valuable model to investigate underlying disease mechanisms from preclinical stages. Excitatory neuron loss in these sheep is markedly regional, localized early reactive changes accurately predicting neuron loss and subsequent symptom development. This investigation of GABAergic interneuron loss revealed similar regional effects that correlate with symptoms. Loss of parvalbumin positive neurons from the affected cortex was apparent at four months and became profound by 19 months, as was somatostatin positive neuron loss to a lesser extent. Conversely calbindin and neuropeptide Y positive neurons were relatively preserved and calretinin staining temporarily increased. Staining of subcortical regions was more intense but subcortical architecture remained relatively intact. Discrete subcortical changes followed from cortical changes in interconnected regions. These data highlight cellular location and interconnectivity as the major determinants of neuron survival, rather than phenotype.

Original languageEnglish
Pages (from-to)50-65
Number of pages16
JournalNeurobiology of Disease
Volume32
Issue number1
DOIs
StatePublished - Oct 2008

Keywords

  • Batten disease
  • CLN6
  • GABAergic interneurons
  • Lysosomal storage disease
  • Neuronal ceroid lipofuscinosis
  • Ovine model

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