title: Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.
abstract: 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.
authors.affiliation: Zilkha Neurogenetics Institute, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Shenfeng
authors.initials: S
authors.lastname: Qiu
authors.forename: Charles T
authors.initials: CT
authors.lastname: Anderson
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
authors.forename: Gordon M G
authors.initials: GM
authors.lastname: Shepherd
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology*; D001931:Brain Mapping; D055724:Electrophysiological Phenomena; D005625:Frontal Lobe / Q000503:physiopathology; D017353:Gene Deletion; D005917:Globus Pallidus / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000503:physiopathology*; D010775:Photic Stimulation; D011149:Pons / Q000503:physiopathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D017966:Pyramidal Cells / Q000503:physiopathology; D015398:Signal Transduction; D013569:Synapses
chemical_list: D018698:Glutamic Acid; D019859:Proto-Oncogene Proteins c-met