Putative microcircuit-level substrates for attention are disrupted in mouse models of autism

Details

• Alternative Title:
  Biol Psychiatry
• Personal Author:
  Luongo, Francisco ; Horn, Meryl ; Sohal, Vikaas S.
• Description:
  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 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 (50-100) neurons simultaneously, in order 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 (VPA) in utero and FMR1 KO 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 VPA-exposed and FMR1 KO mice, but intact following other manipulations which do 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.
• Subjects:
  • Article
  • calcium imaging
  • GCaMP
  • prefrontal cortex
  • Fragile X syndrome
  • acetylcholine
  • valproic acid
  • Action Potentials
  • Animals
  • Attention
  More +
• Source:
  Biol Psychiatry. 79(8):667-675.
• Pubmed ID:
  26022075
• Pubmed Central ID:
  PMC4624609
• Document Type:
  Journal Article
• Funding:
  R00MH085946/MH/NIMH NIH HHS/United States ; DP2MH10001101/DP/NCCDPHP CDC HHS/United States ; DP2 MH100011/MH/NIMH NIH HHS/United States ; R00 MH085946/MH/NIMH NIH HHS/United States ; R25 GM056847/GM/NIGMS NIH HHS/United States ; R25GM56847/GM/NIGMS NIH HHS/United States
• Volume:
  79
• Issue:
  8
• Download URL:
  https://stacks.cdc.gov/view/cdc/40402/cdc_40402_DS1.pdf
• File Type:
  [PDF - 941.44 KB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:c935f1423c0ffa3c55862f346e0fb8f7ac1db17f6b6646a4be9e071a2c64588e