Excitation-inhibition imbalance in Neurexin-1α mutant mice is rescued by administering arbaclofen

Background Altered sensory information processing and disrupted sleep are integral parts of the autism spectrum disorder (ASD) diagnosis. Especially various forms of habituation seem affected, and both hyper- and hypo-sensitivity have been reported in humans. The underlying mechanisms are not well-described however recent studies indicate that an imbalance between excitatory and inhibitory mechanisms may underlie the behavioural characteristics of ASD. The Neurexin-1 ( NRXN1) gene is a risk gene for autism, and has previously been shown to alter signal transmission in mice by increasing neuronal excitation. Methods In this study the functional relationship between Nrxn1 and sensory information processing is investigated over the course of neurodevelopment by testing visual and auditory gating in male, littermate wildtype (WT), heterozygous (Het) and homozygous (Hom) Neurexin-1α deficient mice using in vivo electrophysiology. Furthermore, we studied whether pharmacological modulation of the excitation-inhibition (E/I) balance using arbaclofen a GABA-b agonist, could alter the sensory phenotypes in these mice. Results In characterising the consequences of knocking out the Nrxn1α gene we showed that Hom mice were being sensitized to light flashes compared to the WT. Arbaclofen revealed dose-dependent reversal or sometimes worsening of the vision related phenotypes. Interestingly, in the relation between sensory responses and sleep parameters: we found a correlation between the gating response and vigilance state, and showed sleep intensity and power spectral density of sleep spindles changing as a function of Nrxn1α deficiency. Limitations This study only uses male mice however hormonal differences are very likely to impact the phenotype related to Nrxn1α deficiency. Conclusion These findings highlight the role of Nrxn1α in regulating sensory and sleep phenotypes via excitation/inhibition (E/I) imbalance, emphasizing the dynamic and complex mechanisms underlying ASD-related phenotypes.