Putative microcircuit-level substrates for attention are disrupted in mouse models of autism
Published Date:Apr 28 2015
Source:Biol Psychiatry. 79(8):667-675.
Disease Models, Animal
Fragile X Mental Retardation Protein
Fragile X Syndrome
Mice, Inbred C57BL
Nerve Tissue Proteins
Tissue Culture Techniques
Voltage-Sensitive Dye Imaging
Pubmed Central ID:PMC4624609
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
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.
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.
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.
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.
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