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Recent insights into IQSEC2 disease are summarized in this review as follows: (1) Exome sequencing of IQSEC2 patient DNA has led to the identification of numerous missense mutations that delineate at least six and possibly seven essential functional domains present in the IQSEC2 gene. (2) Experiments using IQSEC2 transgenic and knockout (KO) mouse models have recapitulated the presence of autistic-like behavior and epileptic seizures in affected animals; however, seizure severity and etiology appear to vary considerably between models. (3) Studies in IQSEC2 KO mice reveal that IQSEC2 is involved in inhibitory as well as stimulatory neurotransmission. The overall picture appears to be that mutated or absent IQSEC2 arrests neuronal development, resulting in immature neuronal networks. Subsequent maturation is aberrant, leading to increased inhibition and reduced neuronal transmission. (4) The levels of Arf6-GTP remain constitutively high in IQSEC2 knockout mice despite the absence of IQSEC2 protein, indicating impaired regulation of the Arf6 guanine nucleotide exchange cycle. (5) A new therapy that has been shown to reduce the seizure burden for the IQSEC2 A350V mutation is heat treatment. Induction of the heat shock response may be responsible for this therapeutic effect.

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AbstractΔ9-Tetrahydrocannabinol (Δ9-THC) inhibits tics in individuals with Tourette syndrome (TS). Δ9-THC has similar affinities for CB1/CB2 cannabinoid receptors. However, the effect of HU-308, a selective CB2 receptor agonist, on repetitive behaviors has not been investigated. The effects of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced motor-like tics and Δ9-THC were studied with gene analysis. The effects of HU-308 on head twitch response (HTR), ear scratch response (ESR), and grooming behavior were compared between wildtype and CB2 receptor knockout (CB2−/−) mice, and in the presence/absence of DOI or SR141716A, a CB1 receptor antagonist/inverse agonist. The frequency of DOI-induced repetitive behaviors was higher in CB2−/− than in wildtype mice. HU-308 increased DOI-induced ESR and grooming behavior in adult CB2−/− mice. In juveniles, HU-308 inhibited HTR and ESR in the presence of DOI and SR141716A. HU-308 and beta-caryophyllene significantly increased HTR. In the left prefrontal cortex, DOI increased transcript expression of the CB2 receptor and GPR55, but reduced fatty acid amide hydrolase (FAAH) and α/β-hydrolase domain-containing 6 (ABHD6) expression levels. CB2 receptors are required to reduce 5-HT2A/2C-induced tics in adults. HU-308 has an off-target effect which increases 5-HT2A/2C-induced motor-like tics in adult female mice. The increased HTR in juveniles induced by selective CB2 receptor agonists suggests that stimulation of the CB2 receptor may generate motor tics in children. Sex differences suggest that the CB2 receptor may contribute to the prevalence of TS in boys. The 5-HT2A/2C-induced reduction in endocannabinoid catabolic enzyme expression level may explain the increased endocannabinoids’ levels in patients with TS.

Purposeful induction of fever for healing, including the treatment of epilepsy, was used over 2000 years ago by Hippocrates. More recently, fever has been demonstrated to rescue behavioral abnormalities in children with autism. However, the mechanism of fever benefit has remained elusive due in large part to the lack of appropriate human disease models recapitulating the fever effect. Pathological mutations in the IQSEC2 gene are frequently seen in children presenting with intellectual disability, autism and epilepsy. We recently described a murine A350V IQSEC2 disease model, which recapitulates important aspects of the human A350V IQSEC2 disease phenotype and the favorable response to a prolonged and sustained rise in body core temperature in a child with the mutation. Our goal has been to use this system to understand the mechanism of fever benefit and then develop drugs that can mimic this effect and reduce IQSEC2-associated morbidity. In this study, we first demonstrate a reduction in seizures in the mouse model following brief periods of heat therapy, similar to what was observed in a child with the mutation. We then show that brief heat therapy is associated with the correction of synaptic dysfunction in neuronal cultures of A350V mice, likely mediated by Arf6-GTP.