The sensory profile of Nrxn1α gene knockout mice based on local field potentials

Autism spectrum disorder (ASD) is a neurodevelopmental disorder having detrimental impact on peoples’ lives, affecting around 1% of a population. In order to try and understand what people with ASD are perceiving in the world around them, there is a need to study the underlying mechanisms, such as deficits in sensory processing. Nrxn1 is a well-conserved gene across species and one of the largest genes in the human genome. Parts of this gene have been found to be deleted in several cases of ASD. It encodes a presynaptic cell-adhesion molecule and is believed to act in synaptic transmission. Previous studies have found a discrete electrophysiological phenotype in Nrxn1α gene knock-out mice [1]. This electrophysiological phenotype was a change in excitatory currents. Further behavioral abnormalities in acoustic paired-pulse inhibition have been reported [2]. To study the sensory consequences of altered Nrxn1α expression male mice of the three genotypes homozygous and heterozygous gene knock-out, and wildtype littermates underwent surgery for implantation of recording electrodes in the visual cortex, the auditory cortex and the prefrontal cortex. In a longitudinal design the animals were exposed to a battery of electrophysiological tests to follow the development of the phenotype. The overall statistics of the event-related potentials have been analyzed for the visual evoked potentials (VEP), auditory evoked potentials (AEP) and steady-state VEP (SSVEP). All three paradigms showed an increase of amplitude as a function of age. For VEP and AEP the amplitudes were extracted for each peak of the waveforms. The VEP has seven peaks named according to their deflection either positive (P) or negative (N) and their succession. Testing the VEP data for effect of time and gene using a two-way ANOVA, showed no effect of genotype, but an effect of time on P2 (p=0.006), N2 (p<0.00001), P3 (p<0.00001) and N3 (p<0.00001) after adjusting for multiple comparisons. For the AEP there was an effect of time on all peaks P1 (p<0.00001), N1 (p=0.0018), P2 (p<0.00001), N2 (p<0.00001) and P3 (p=0.011) and an effect of genotype on N1 (p= 0.0014), P2 (p= 0.0092) and N2 (p=0.00023). The power of the steady-state response was extracted from the power band belonging to the second harmonic. This was statistically tested using a two-way ANOVA of time and genotype. There was no interaction of time and genotype (F(6,103)=2.1, p=0.06), but a clear effect of time (F(1,35)=8.6, p=0.005). Though, there seemed to be a macroscopic effect with the power of the KO being lower at the first to time points. This turned out to not be statistically significant (F(2,35)=1.6, p=0.21). These results suggest that local field potentials can detect developmental effects that were irrespective of genotype. However, the in-depth analysis is still in progress, as are the analyses of gating data both visual and auditory along with latency data and the resting state data. Interestingly, Nrxn1α genotype alters primary auditory sensory processing in the AEP indicating that this specific sensory modality may be affected as a function of genotype.