Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes

Autism Res. 2013 Apr;6(2):69-77. doi: 10.1002/aur.1264. Epub 2013 Feb 25.


Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism. Autism Res 2013, 6: 69-77. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

Keywords: NMDA receptor 1 knockout; animal models; autism; electrophysiology; endophenotype.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acoustic Stimulation / methods
  • Animals
  • Autistic Disorder / physiopathology*
  • Behavior, Animal / physiology
  • Disease Models, Animal*
  • Electroencephalography / methods
  • Evoked Potentials / physiology
  • Interneurons / metabolism*
  • Mice
  • Mice, Knockout
  • Parvalbumins*
  • Phenotype
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Vocalization, Animal / physiology


  • NMDA receptor A1
  • Parvalbumins
  • Receptors, N-Methyl-D-Aspartate