期刊
JOURNAL OF COMPARATIVE NEUROLOGY
卷 518, 期 21, 页码 4463-4478出版社
WILEY
DOI: 10.1002/cne.22467
关键词
Met receptor tyrosine kinase signaling; Emx1(Cre)/Met(fx/fx); autism-spectrum disorders; anterior cingulate cortex
资金
- National Institute of Mental Health [MH067842]
- National Institute of Child Health and Human Development [P30 HD15052]
- National Institute on Drug Abuse [DA022785]
- Simons Foundation
Human genetic findings and murine neuroanatomical expression mapping have intersected to implicate Met receptor tyrosine kinase signaling in the development of forebrain circuits controlling social and emotional behaviors that are atypical in autism-spectrum disorders (ASD). To clarify roles for Met signaling during forebrain circuit development in vivo, we generated mutant mice (Emx1(Cre)/Met(fx/fx)) with an Emx1-Cre-driven deletion of signaling-competent Met in dorsal pallially derived forebrain neurons. Morphometric analyses of Lucifer yellow-injected pyramidal neurons in postnatal day 40 anterior cingulate cortex (ACC) revealed no statistically significant changes in total dendritic length but a selective reduction in apical arbor length distal to the soma in Emx1(Cre)/Met(fx/fx) neurons relative to wild type, consistent with a decrease in the total tissue volume sampled by individual arbors in the cortex. The effects on dendritic structure appear to be circuit-selective, insofar as basal arbor length was increased in Emx1(Cre)/Met(fx/fx) layer 2/3 neurons. Spine number was not altered on the Emx1(Cre)/Met(fx/fx) pyramidal cell populations studied, but spine head volume was significantly increased (similar to 20%). Cell-nonautonomous, circuit-level influences of Met signaling on dendritic development were confirmed by studies of medium spiny neurons (MSN), which do not express Met but receive Met-expressing corticostriatal afferents during development. Emx1(Cre)/Met(fx/fx) MSN exhibited robust increases in total arbor length (similar to 20%). As in the neocortex, average spine head volume was also increased (similar to 12%). These data demonstrate that a developmental loss of presynaptic Met receptor signaling can affect postsynaptic morphogenesis and suggest a mechanism whereby attenuated Met signaling could disrupt both local and long-range connectivity within circuits relevant to ASD. J. Comp. Neurol. 518: 4463-4478, 2010. (C) 2010 Wiley-Liss, Inc.
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