Knockout of NMDA Receptors in Parvalbumin Interneurons Recreates Autism‐Like Phenotypes

Abstract

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.

Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2

“…Further, our pharmacological data support dysregulation of GABAergic and glutamatergic signaling in mutants. Altered NMDA signaling has been shown to cause GABAergic deficits, particularly in parvalbumin-positive (PV+) interneurons, and has been proposed as a mechanism underlying neuropsychiatric disorders (Keilhoff et al, 2004; Saunders et al, 2013). Moreover, mouse Cntnap2 knockouts display GABAergic deficits, most prominently in PV+ interneurons (Penagarikano et al, 2011).…”

Neuromagnetic Oscillations Predict Evoked-Response Latency Delays and Core Language Deficits in Autism Spectrum Disorders

“…In ASD, a growing body of research has shown GABA receptors to be downregulated in ASD (Fatemi et al 2009), and ASD participants have shown decreased gamma-band oscillatory activity compared to controls (Wilson et al 2007; Rojas et al 2008; Orekhova et al 2007). Interneurons defined by the fast-spiking phenotype and expression of the calcium-binding protein parvalbumin have been implicated in gamma oscillations (e.g., (Tamas et al 2000; Whittington et al 1995), and in vivo mouse studies show that inhibiting parvalbumin interneurons suppresses gamma oscillations whereas driving these interneurons is sufficient to generate emergent gamma oscillations (Saunders et al 2013; Sohal et al 2009). With regard to the pre-stimulus group differences observed in the present study, it is worth noting that optogenetic inhibition of fast-spiking interneurons reduced stimulus-evoked gamma synchrony and also caused an increase in baseline LFP power in the absence of a stimulus (2013).…”

Specific Roles of NMDA Receptor Subunits in Mental Disorders

“…Autism has been reliably associated with electrophysiological endophenotypes that may be caused by NMDA receptor disruption on parvalbumin (PV)-containing interneurons [133]. In human, M1 (N1 event-related potential as measured by magneto-encephalography) latency is shifted by approximately 10% in ASD patients [134].…”

“…The N1 event-related potential is a negative peak approximately 100 ms after sensory stimulation that is linked to early attention [135]. In PV containing cell-type selective GluN1 KO mice, delayed N1 event-related potential latency, reduced sociability, and impairment of mating-related USVs are observed [133]. In mice, social behavior is known to be expressed as social investigation, intermale aggression, sexual behavior, and parental behavior.…”

“…In mice, social behavior is known to be expressed as social investigation, intermale aggression, sexual behavior, and parental behavior. When aggressive behavior or sexual motivation of the test mouse toward the stimulus mouse is low in the social interaction test, a significant correlation is found between delayed N1 latency and reduced sociability (i.e., social approach with same-sex gonadectomized mouse) but not between N1 latency and premating USV power (i.e., social approach with female mouse) or T-maze performance [133]. Reduced sociability is one of core symptoms in the patients of ASD [134].…”