Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism
Maria T. Lazaro,
Jiannis Taxidis,
Tristan Shuman,
Iris Bachmutsky,
Taruna Ikrar,
Rommel Santos,
G. Mark Marcello,
Apoorva Mylavarapu,
Swasty Chandra,
Allison Foreman,
Rachna Goli,
Duy Tran,
Nikhil Sharma,
Michelle Azhdam,
Hongmei Dong,
Katrina Y. Choe,
Olga Peñagarikano,
Sotiris C. Masmanidis,
Bence Rácz,
Xiangmin Xu,
Daniel H. Geschwind,
Peyman Golshani
Affiliations
Maria T. Lazaro
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
Jiannis Taxidis
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
Tristan Shuman
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
Iris Bachmutsky
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Taruna Ikrar
Department of Anatomy and Neurobiology, UC Irvine, Irvine, CA, USA
Rommel Santos
Department of Anatomy and Neurobiology, UC Irvine, Irvine, CA, USA
G. Mark Marcello
Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary
Apoorva Mylavarapu
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Swasty Chandra
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Allison Foreman
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Rachna Goli
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Duy Tran
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Nikhil Sharma
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Michelle Azhdam
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Hongmei Dong
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Katrina Y. Choe
Center for Neurobehavioral Genetics, Semel Institute, UCLA, Los Angeles, CA, USA
Olga Peñagarikano
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
Sotiris C. Masmanidis
Integrative Center for Learning and Memory, Brain Research Institute, UCLA, Los Angeles, CA, USA
Bence Rácz
Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary
Xiangmin Xu
Department of Anatomy and Neurobiology, UC Irvine, Irvine, CA, USA
Daniel H. Geschwind
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; Corresponding author
Peyman Golshani
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; Corresponding author
Summary: 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. : Lazaro et al. demonstrate a decrease in synaptic inputs onto mPFC L2/3 pyramidal neurons of Cntnap2 KO mice, concurrent with reduced spines and synapses. These lead to perturbed network activity, with mPFC cells exhibiting reduced phase locking and altered preferred phases to slow LFP oscillations, which may underlie autism-related phenotypes. Keywords: oscillation, delta, theta, phase-locking, inhibition, brain state, connectivity, functional, biomarker, EEG
