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 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.

Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model

“…The fact that two mouse models with opposite molecular and cellular phenotypes produce the same circuit-level phenotype raises the possibility that our findings may be generalizable to other forms of syndromic intellectual disabilities. Indeed, hypersynchrony in the developing neocortex and increased correlations in the prefrontal cortex were also observed in two other mouse models of autism (Goncalves et al, 2013; Luongo et al, 2015). …”

“…Impairment in these mechanisms leads to a loss of the asynchronous network state, resulting in populations of neurons firing in synchrony (Uhlhaas and Singer, 2006), even in the absence of stimulation at the baseline state. Excessive neuronal population synchrony disrupts complex circuit dynamics, impairing normal information processing (Goncalves et al, 2013; Luongo et al, 2015). …”

Preparation of Acute Brain Slices Using an Optimized <em>N</em>-Methyl-D-glucamine Protective Recovery Method

“…These acute slice studies span neocortical 3 17 18 , hippocampal 15 19 20 21 , striatal 22 23 24 , midbrain 25 26 27 28 29 , and hindbrain 30 31 32 33 34 regions, and a variety of neurotransmitter and neuromodulator types including glutamatergic 4 30 , GABAergic 18 20 31 35 36 , dopaminergic 24 29 37 38 , cholinergic 14 37 38 39 , noradrenergic 40 , and serotonergic 27 28 neurotransmission. The method is also well suited for optogenetic control of neuronal activity in slices derived from transgenic animals 3 39 or following in vivo viral injections 17 27 28 40 41 42 43 , as well as functional Ca 2+ imaging of neuronal activity 2 44 45 46 . Analyses of both short term plasticity 4 47 48 and diverse forms of long-term plasticity 16 35 48 have been reported.…”

Meynert’s Nucleus Complex White Matter Abnormalities in Autism Spectrum Disorders: An MRI Study

“…It has been therefore proposed that the attentional deficits observed in ASD might be linked to disruptions of the cholinergic modulation by acting on local cortical microcircuits to disconnect spontaneous activity. Defects in this mechanism might represent endophenotypes that could link diverse genetic and developmental disruptions to attentional deficits in ASD [10].…”

“…Notwithstanding these speculations, it has not been fully clarified yet which specific circuits' abnormalities might affect the cholinergic system of subjects with ASD [10]. A loss of cortical and deep grey matter nicotinic acetylcholine receptors has been shown in autistic subjects as well [4,6], leading to preclinical studies, which tested the use of nicotine to reduce aggression-related behaviours [11].…”