Dataset Information

Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism.

ABSTRACT: Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice. However, the functional effects of these mutations at cellular and circuit levels remain elusive. Using laser-scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of Cntnap2 knockout (KO) mice, concurrent with reduced spines and synapses, despite normal dendritic complexity and intrinsic excitability. Moreover, recording of mPFC local field potentials (LFPs) and unit spiking in vivo revealed increased activity in inhibitory neurons, reduced phase-locking to delta and theta oscillations, and delayed phase preference during locomotion. Excitatory neurons showed similar phase modulation changes at delta frequencies. Finally, pairwise correlations increased during immobility in KO mice. Thus, reduced synaptic inputs can yield perturbed temporal coordination of neuronal firing in cortical ensembles.

SUBMITTER: Lazaro MT

PROVIDER: S-EPMC6553483 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism.

Lazaro Maria T MT Taxidis Jiannis J Shuman Tristan T Bachmutsky Iris I Ikrar Taruna T Santos Rommel R Marcello G Mark GM Mylavarapu Apoorva A Chandra Swasty S Foreman Allison A Goli Rachna R Tran Duy D Sharma Nikhil N Azhdam Michelle M Dong Hongmei H Choe Katrina Y KY Peñagarikano Olga O Masmanidis Sotiris C SC Rácz Bence B Xu Xiangmin X Geschwind Daniel H DH Golshani Peyman P

Cell reports 20190501 9

Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice. However, the functional effects of these mutations at cellular and circuit levels remain elusive. Using laser-scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of ...[more]

PMID: 31141683

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Project description:Autism spectrum disorder is increasingly associated with atypical perceptual and sensory symptoms. Here we explore the hypothesis that aberrant sensory processing in autism spectrum disorder could be linked to atypical intra- (local) and interregional (global) brain connectivity. To elucidate oscillatory dynamics and connectivity in the visual domain we used magnetoencephalography and a simple visual grating paradigm with a group of 18 adolescent autistic participants and 18 typically developing control subjects. Both groups showed similar increases in gamma (40-80 Hz) and decreases in alpha (8-13 Hz) frequency power in occipital cortex. However, systematic group differences emerged when analysing intra- and interregional connectivity in detail. First, directed connectivity was estimated using non-parametric Granger causality between visual areas V1 and V4. Feedforward V1-to-V4 connectivity, mediated by gamma oscillations, was equivalent between autism spectrum disorder and control groups, but importantly, feedback V4-to-V1 connectivity, mediated by alpha (8-13 Hz) oscillations, was significantly reduced in the autism spectrum disorder group. This reduction was positively correlated with autistic quotient scores, consistent with an atypical visual hierarchy in autism, characterized by reduced top-down modulation of visual input via alpha-band oscillations. Second, at the local level in V1, coupling of alpha-phase to gamma amplitude (alpha-gamma phase amplitude coupling) was reduced in the autism spectrum disorder group. This implies dysregulated local visual processing, with gamma oscillations decoupled from patterns of wider alpha-band phase synchrony (i.e. reduced phase amplitude coupling), possibly due to an excitation-inhibition imbalance. More generally, these results are in agreement with predictive coding accounts of neurotypical perception and indicate that visual processes in autism are less modulated by contextual feedback information.

Dataset Information

Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism.

Publications

Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism.

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