Conserved GABA/GAMMA Coupling Is Seen in a Translational Preclinical Model That Recapitulate a Key Aspect of ASD
Autism spectrum disorders (ASD) have been hypothesized to arise from an imbalance of excitation and inhibition (E/I imbalance). In both clinical and preclinical studies, E/I imbalance has been repeatedly observed using a wide range of techniques. One result of E/I imbalance could be altered gamma-band activity (GAMMA), which is thought to be heavily reliant on inhibition for its generation. Accordingly, concurrent to the E/I imbalance findings, alterations to GAMMA are present across modalities in ASD, being recapitulated by multiple independent groups. These GAMMA deficits are also present in preclinical models recreating key aspects of ASD.
In healthy adults GAMMA is related to GABAergic tone in both motor and visual systems, though not without controversy. Preliminary work suggests this is also true for the auditory system, and that concomitant decreases in both GABA and GAMMA are present in ASD within the same participants. Furthermore, the biological coupling of neurochemistry and neuronal GAMMA activity is conserved is ASD. What remains to be known is if this GABA/GAMMA coupling seen in humans translates to pre-clinical phenotypes (as with E/I imbalance and GAMMA activity separately).
Determine if the GABA/GAMMA coupling seen in the auditory system of both typically developing participants and participants with ASD, is recreated in an animal model that recreates a key aspect of ASD.
Magnetoencephalography (MEG) and magnetic resonance spectroscopy (MRS) was used to record neuronal activity and GABAergic tone (respectively) in both typically developing participants and participants with ASD. This was contrasted to translational pre-clinical findings from an animal model that recapitulates key aspects of ASD (Protocadherin 10 heterozygous mice [PCDH10 +/-]) and their wild-type counterparts. In-vivo electroencephalography (EEG) and high performance liquid chromatography (HPLC) recorded neuronal responses and inhibitory tone in these mice respectively. To allow for comparison of electrophysiological data, near identical analyses are implemented for both clinical and pre-clinical data.
GABA and GAMMA are correlated in both typically developing participants and participants with ASD (R2TD=0.31, p<0.05; R2ASD=0.13, p<0.05), with no difference between group level regression slopes (difference in slope of regression p>0.1). While separating based on genotype was not possible due to insufficient sample size, GABA and GAMMA appear correlated in PCDH10 +/- and their wild-type counterparts (R2 =0.41, p<0.05).
Typically developing participants and participants with ASD demonstrate an association between GABA and GAMMA, with the coupling conserved between groups. A pre-clinical murine model of ASD and their wild type counterparts also demonstrated such a relationship, suggesting this phenotype is conversed across species. Further study is needed to determine if within group associations of GABA and GAMMA differ between PCDH10 +/- mice and their wild type counterparts.