Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice

Hum Mol Genet. 2012 May 1;21(9):1954-67. doi: 10.1093/hmg/dds005. Epub 2012 Jan 18.


Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6-/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6-/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD.

Publication types

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

MeSH terms

  • Aging / pathology
  • Aging / physiology
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / pathology
  • Animals
  • Apoptosis / physiology
  • Base Sequence
  • Behavior, Animal / physiology
  • Brain / enzymology
  • Brain / pathology
  • Caspase 6 / deficiency
  • Caspase 6 / genetics
  • Caspase 6 / physiology*
  • Humans
  • Huntington Disease / enzymology
  • Huntington Disease / pathology
  • Mice
  • Mice, Knockout
  • Motor Activity / physiology
  • Nerve Degeneration / enzymology*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Neurons / enzymology
  • Neurons / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology


  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • Casp6 protein, mouse
  • Caspase 6