Role of astrocytic inwardly-rectifying K+ channels in the pathogenesis of Autism Spectrum Disorders with susceptibility to seizures (Autism-Epilepsy Phenotype)

Autism spectrum disorders (ASD) are developmental brain disorders characterized by variable degrees of impairment in social interaction and communication, and by restricted, stereotyped, and repetitive interests and behaviors. Children with ASD are at high risk for developing seizures. On the other hand, the prevalence of autism in children with epilepsy is approximately 32%, about 50 times higher than in the general population. Thus, ASD and epilepsy are strongly correlated conditions and when associated define a subgroup of patients, that is, the "Autism-Epilepsy Phenotype (AEP)". It is possible that both ASD and epilepsy share common pathogenetic mechanisms residing in disturbed glial ion channels for potassium (Kir channels). We propose to assess if and how astrocytic Kir channels play a direct role in the etiopathogenesis of AEP through the following aims: (1) to expand the clinical and genetic investigations in patients with AEP by analyzing for mutations the KCNJ10, KCNJ16, and KCNJ2 genes; (2) to study the functional effects of mutations on channel activity both in vitro and in vivo; and (3) to correlate the clinical spectrum with the genetic findings. Our project might offer new insight into the mechanisms of both ASD and epilepsy. This would improve the diagnosis, genetic counseling, and treatment of these disorders opening new perspectives for the development of new pharmacological strategies.