title: Putative Microcircuit-Level Substrates for Attention Are Disrupted in Mouse Models of Autism.
abstract: BACKGROUND
  Deep layer excitatory circuits in the prefrontal cortex represent the strongest locus for genetic convergence in autism, but specific abnormalities within these circuits that mediate key features of autism, such as cognitive or attentional deficits, remain unknown. Attention normally increases the sensitivity of neural populations to incoming signals by decorrelating ongoing cortical circuit activity. Here, we investigated whether mechanisms underlying this phenomenon might be disrupted within deep layer prefrontal circuits in mouse models of autism.
  
  
  METHODS
  We isolated deep layer prefrontal circuits in brain slices then used single-photon GCaMP imaging to record activity from many (50 to 100) neurons simultaneously to study patterns of spontaneous activity generated by these circuits under normal conditions and in two etiologically distinct models of autism: mice exposed to valproic acid in utero and Fmr1 knockout mice.
  
  
  RESULTS
  We found that modest doses of the cholinergic agonist carbachol normally decorrelate spontaneous activity generated by deep layer prefrontal networks. This effect was disrupted in both valproic acid-exposed and Fmr1 knockout mice but intact following other manipulations that did not model autism.
  
  
  CONCLUSIONS
  Our results suggest that cholinergic modulation may contribute to attention by acting on local cortical microcircuits to decorrelate spontaneous activity. Furthermore, defects in this mechanism represent a microcircuit-level endophenotype that could link diverse genetic and developmental disruptions to attentional deficits in autism. Future studies could elucidate pathways leading from various etiologies to this circuit-level abnormality or use this abnormality itself as a target and identify novel therapeutic strategies that restore normal circuit function.
authors.affiliation: Department of Psychiatry (FL, VSS), University of California, San Francisco, San Francisco, California.; Center for Integrative Neuroscience (FL, VSS), University of California, San Francisco, San Francisco, California.; Sloan-Swartz Center for Theoretical Neurobiology (FL, VSS), University of California, San Francisco, San Francisco, California.; Neuroscience Graduate Program (FL, MH), University of California, San Francisco, San Francisco, California.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Luongo
authors.affiliation: Neuroscience Graduate Program (FL, MH), University of California, San Francisco, San Francisco, California.
authors.forename: Meryl E
authors.initials: ME
authors.lastname: Horn
authors.affiliation: Department of Psychiatry (FL, VSS), University of California, San Francisco, San Francisco, California.; Center for Integrative Neuroscience (FL, VSS), University of California, San Francisco, San Francisco, California.; Sloan-Swartz Center for Theoretical Neurobiology (FL, VSS), University of California, San Francisco, San Francisco, California.. Electronic address: vikaas.sohal@ucsf.edu.
authors.forename: Vikaas S
authors.initials: VS
authors.lastname: Sohal
mesh_terms: D000200:Action Potentials; D000818:Animals; D001288:Attention / Q000502:physiology*; D001321:Autistic Disorder / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005473:Fluoxetine; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014635:Valproic Acid; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D002118:Calcium; D005473:Fluoxetine; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D014635:Valproic Acid; C498794:Disc1 protein, mouse; C497684:Fmr1 protein, mouse
keywords: Acetylcholine; Calcium imaging; Fragile X syndrome; GCaMP; Prefrontal cortex; Valproic acid