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Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium-derived, conditional knock-out (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes, this pathway was stronger by a factor of approximately 2. This increase was both sublayer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.

Pubmed ID: 21490227


  • Qiu S
  • Anderson CT
  • Levitt P
  • Shepherd GM


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

Publication Data

April 13, 2011

Associated Grants

  • Agency: NIMH NIH HHS, Id: K99MH087628
  • Agency: NIMH NIH HHS, Id: R01 MH067842
  • Agency: NINDS NIH HHS, Id: R01 NS061963
  • Agency: NIMH NIH HHS, Id: R01MH067842
  • Agency: NINDS NIH HHS, Id: R01NS061963
  • Agency: NINDS NIH HHS, Id: T32NS041234

Mesh Terms

  • Animals
  • Autistic Disorder
  • Brain Mapping
  • Electrophysiological Phenomena
  • Frontal Lobe
  • Gene Deletion
  • Globus Pallidus
  • Glutamic Acid
  • Image Processing, Computer-Assisted
  • Mice
  • Mice, Knockout
  • Neural Pathways
  • Photic Stimulation
  • Pons
  • Proto-Oncogene Proteins c-met
  • Pyramidal Cells
  • Signal Transduction
  • Synapses