title: Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome.
abstract: Multiple autism risk genes converge on the regulation of mTOR signalling, which is a key effector of neuronal growth and connectivity. We show that mTOR signalling is dysregulated during early postnatal development in the cerebral cortex of germ-line heterozygous Pten mutant mice (Pten+/-), which model macrocephaly/autism syndrome. The basolateral amygdala (BLA) receives input from subcortical-projecting neurons in the medial prefrontal cortex (mPFC). Analysis of mPFC to BLA axonal projections reveals that Pten+/-mice exhibit increased axonal branching and connectivity, which is accompanied by increased activity in the BLA in response to social stimuli and social behavioural deficits. The latter two phenotypes can be suppressed by pharmacological inhibition of S6K1 during early postnatal life or by reducing the activity of mPFC-BLA circuitry in adulthood. These findings identify a mechanism of altered connectivity that has potential relevance to the pathophysiology of macrocephaly/autism syndrome and autism spectrum disorders featuring dysregulated mTOR signalling.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA.|The Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute, USA.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA.|The Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute, USA.
authors.forename: Damon T
authors.initials: DT
authors.lastname: Page
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000503:physiopathology*; D066272:Basolateral Nuclear Complex / Q000503:physiopathology*; D004195:Disease Models, Animal; D019066:Facies; D005260:Female; D006801:Humans; D008297:Male; D058627:Megalencephaly / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009415:Nerve Net / Q000503:physiopathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000503:physiopathology*; D011247:Pregnancy; D015398:Signal Transduction; D012919:Social Behavior; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse