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Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death.

Agrin-deficient mice die at birth because of aberrant development of the neuromuscular junctions. Here, we examined the role of agrin at brain synapses. We show that agrin is associated with excitatory but not inhibitory synapses in the cerebral cortex. Most importantly, we examined the brains of agrin-deficient mice whose perinatal death was prevented by the selective expression of agrin in motor neurons. We find that the number of presynaptic and postsynaptic specializations is strongly reduced in the cortex of 5- to 7-week-old mice. Consistent with a reduction in the number of synapses, the frequency of miniature postsynaptic currents was greatly decreased. In accordance with the synaptic localization of agrin to excitatory synapses, changes in the frequency were only detected for excitatory but not inhibitory synapses. Moreover, we find that the muscle-specific receptor tyrosine kinase MuSK, which is known to be an essential component of agrin-induced signaling at the neuromuscular junction, is also localized to a subset of excitatory synapses. Finally, some components of the mitogen-activated protein (MAP) kinase pathway, which has been shown to be activated by agrin in cultured neurons, are deregulated in agrin-deficient mice. In summary, our results provide strong evidence that agrin plays an important role in the formation and/or the maintenance of excitatory synapses in the brain, and we provide evidence that this function involves MAP kinase signaling.

Pubmed ID: 17611272

Authors

  • Ksiazek I
  • Burkhardt C
  • Lin S
  • Seddik R
  • Maj M
  • Bezakova G
  • Jucker M
  • Arber S
  • Caroni P
  • Sanes JR
  • Bettler B
  • Ruegg MA

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

July 4, 2007

Associated Grants

None

Mesh Terms

  • Age Factors
  • Agrin
  • Animals
  • Animals, Newborn
  • Cerebral Cortex
  • Chickens
  • Female
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Transgenic
  • Survival Rate
  • Synapses