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Cell Rep. 2019 May 28;27(9):2567-2578.e6. doi: 10.1016/j.celrep.2019.05.006.

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

Author information

1
Interdepartmental Program for Neuroscience, UCLA, Los Angeles, CA, USA; Center for Neurobehavioral Genetics, Semel Institute, UCLA, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
2
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Integrative Center for Learning and Memory, Brain Research Institute, UCLA, Los Angeles, CA, USA.
3
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Integrative Center for Learning and Memory, Brain Research Institute, UCLA, Los Angeles, CA, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
5
Department of Anatomy and Neurobiology, UC Irvine, Irvine, CA, USA.
6
Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary.
7
Center for Neurobehavioral Genetics, Semel Institute, UCLA, Los Angeles, CA, USA.
8
Department of Pharmacology, School of Medicine, University of the Basque Country (UPV/EHU), Vizcaya, Spain; Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Madrid, Spain.
9
Integrative Center for Learning and Memory, Brain Research Institute, UCLA, Los Angeles, CA, USA.
10
Center for Neurobehavioral Genetics, Semel Institute, UCLA, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Center for Autism Research and Treatment, Semel Institute, UCLA, Los Angeles, CA, USA; Intellectual Development and Disabilities Research Center, UCLA, Los Angeles, CA, USA. Electronic address: dhg@mednet.ucla.edu.
11
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Integrative Center for Learning and Memory, Brain Research Institute, UCLA, Los Angeles, CA, USA; Intellectual Development and Disabilities Research Center, UCLA, Los Angeles, CA, USA; West Los Angeles VA Medical Center, Los Angeles, CA. Electronic address: pgolshani@mednet.ucla.edu.

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.

KEYWORDS:

EEG; biomarker; brain state; connectivity; delta; functional; inhibition; oscillation; phase-locking; theta

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