New avenues in molecular genetics for the diagnosis and application of therapeutics to the epilepsies.

Genetic epidemiology studies have shown that most epilepsies involve some genetic cause. In addition, twin studies have helped strengthen the hypothesis that in most patients with epilepsy, a complex inheritance is involved. More recently, with the development of high-density single-nucleotide polymorphism (SNP) microarrays and next-generation sequencing (NGS) technologies, the discovery of genes related to the epilepsies has accelerated tremendously. Especially, the use of whole exome sequencing (WES) has had a considerable impact on the identification of rare genetic variants with large effect sizes, including inherited or de novo mutations in severe forms of childhood epilepsies. The identification of pathogenic variants in patients with these childhood epilepsies provides many benefits for patients and families, such as the confirmation of the genetic nature of the diseases. This process will allow for better genetic counseling, more accurate therapy decisions, and a significant positive emotional impact. However, to study the genetic component of the more common forms of epilepsy, the use of high-density SNP arrays in genome-wide association studies (GWAS) seems to be the strategy of choice. As such, researchers can identify loci containing genetic variants associated with the common forms of epilepsy. The knowledge generated over the past two decades about the effects of the mutations that cause the monogenic epilepsy is tremendous; however, the scientific community is just starting to apply this information in order to generate better target treatments.

Peripheral oxytocin injection modulates vomeronasal sensory activity and reduces pup-directed aggression in male mice.

Behaviors are shaped by hormones, which may act either by changing brain circuits or by modifying sensory detection of relevant cues. Pup-directed behaviors have been previously shown to change via action of hormones at the brain level. Here, we investigated hormonal control of pup-induced activity in the vomeronasal organ, an olfactory sensory structure involved in the detection of non-volatile chemosignals. Vomeronasal activity decreases as males switch from a pup-aggressive state to a non-aggressive parenting state, after they socially contact a female. RNA sequencing, qPCR, and in situ hybridization were used to identify expression, in the vomeronasal sensory epithelium, of candidate GPCR hormone receptors chosen by in silico analyses and educated guesses. After identifying that oxytocin and vasopressin receptors are expressed in the vomeronasal organ, we injected the corresponding hormones in mice and showed that oxytocin administration reduced both pup-induced vomeronasal activity and aggressive behavior. Conversely, injection of an oxytocin receptor antagonist in female-primed male animals, which normally exhibit reduced vomeronasal activity, significantly increased the number of active vomeronasal neurons. These data link oxytocin to the modulation of olfactory sensory activity, providing a possible mechanism for changes in male behavior after social experience with females.