The PI3K signaling pathway as a pharmacological target in Autism related disorders and Schizophrenia

Abstract

This review is focused in PI3K’s involvement in two widespread mental disorders: Autism and Schizophrenia. A largebody of evidence points to synaptic dysfunction as a cause of these diseases, either during the initial phases ofbrain synaptic circuit’s development or later modulating synaptic function and plasticity. Autism related disordersand Schizophrenia are complex genetic conditions in which the identification of gene markers has proved difficult,although the existence of single-gene mutations with a high prevalence in both diseases offers insight into the roleof the PI3K signaling pathway. In the brain, components of the PI3K pathway regulate synaptic formation and plasticity;thus, disruption of this pathway leads to synapse dysfunction and pathological behaviors. Here, we recapitulate recentevidences that demonstrate the imbalance of several PI3K elements as leading causes of Autism and Schizophrenia,together with the plausible new pharmacological paths targeting this signaling pathway.

Developmental deficits, synapse and dendritic abnormalities in a Clcn4 KO autism mice model : Endophenotypic target for ASD

“…These ndings are consistent with previous reports showing that antipsychotics promote neurite outgrowth 47 and neural plasticity 48 through phosphorylation of PSD95 by CDK5-mediated TrkB phosphorylation. TrkB activity stimulates the ERK and PI3K/AKT pathways, representing a potential therapeutic target for psychiatric conditions [70][71][72] . The activity of Synapsin is tightly regulated by several proteins and phosphatases, such as CDK5, which modulate the association of Synapsin with synaptic vesicles, actin laments, and other synaptic proteins 53 .…”