Postsynaptic alteration of NR2A subunit and defective autophosphorylation of alpha CaMKII at Threonine-286 contribute to abnormal plasticity and morphology of upper motor neurons in presymptomatic SOD1 G93A mice, a murine model for amyotrophic lateral sclerosis

A. Spalloni, N. Origlia, C. Sgobio, A. Trabalza, M. Nutini, N. Berretta, G. Bernardi, L. Domenici, M. Ammassari-Teule, P. Longone

Research output: Contribution to journalArticlepeer-review

Abstract

Although amyotrophic lateral sclerosis (ALS) has long been considered as a lower motor neuron (MN) disease, degeneration of upper MNs arising from a combination of mechanisms including insufficient growth factor signaling and enhanced extracellular glutamate levels is now well documented. The observation that these mechanisms are altered in presymptomatic superoxide dismutase (SOD1) mice, an ALS mouse model, suggests that defective primary motor cortex (M1) synaptic activity might precede the onset of motor disturbances. To examine this point, we assessed the composition of AMPAR and NMDAR subunits and of the alphaCa 2+/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction from the M1 in postnatal P80-P85 SOD1 G93A and wild-type mice. We show that presymptomatic SOD1 G93A exhibit a selective decrease of NR2A subunit expression and of the alphaCa 2+/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction of upper MNs synapses. These molecular alterations are associated with synaptic plasticity defects, and a reduction in upper MN dendritic outgrowth revealing that abnormal neuronal connectivity in the M1 region precedes the onset of motor symptoms. We suggest that the progressive disruption of M1 corticocortical connections resulting from the SOD1 G93A mutation might extend to adjacent regions and promote development of cognitive/dementia alterations frequently associated with ALS.

Original languageEnglish
Pages (from-to)796-805
Number of pages10
JournalCerebral Cortex
Volume21
Issue number4
DOIs
Publication statusPublished - Apr 2011

Keywords

  • AMPA and NMDA receptors
  • cortical synaptic plasticity
  • dendrite outgrowth
  • familial amyotrophic lateral sclerosis (fALS)
  • SOD1G93A mutation
  • upper motor neurons

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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