Intersectin1/cdc42 signaling regulates methamphetamine-induced neuronal remodeling in the hippocampus

The development and maintenance of drug addiction triggered by psychoactive substances, such as methamphetamine (Meth), is strongly influenced by synaptic and morphological adaptations in the brain. The hippocampus has a key role in the formation of maladaptive drug-context associations and relapse. However, the mechanisms regulating this complex process are not completely understood. Recent studies highlight that the actin cytoskeleton and its regulatory proteins play a fundamental role in morphological and behavioral plasticity associated with drug use. Here, we show that a binge pattern of Meth administration is sufficient to increase hippocampal neurite outgrowth and dendritic spine density leading to augmented basal synaptic transmission and impaired long-term potentiation (LTP) response. To study the molecular pathways affected by Meth, we used embryonic primary neuron cultures from the hippocampus and performed RNA Sequencing from isolated soma or neurites compartments, FRET microscopy, biochemical analyses, and morphometric measurements of dendrites to demonstrate that intersectin (Itsn)1/cdc42 signaling is an important mediator of Meth-induced morphological adaptations, specifically in the synaptic compartment. Furthermore, AAV-mediated depletion of neuronal cdc42 in the hippocampus prevented Meth-induced changes in cytoarchitecture and their consequent impact on neuronal functionality. Our results highlight relevant compartment-associated changes in the activity of Itsn1/cdc42 pathway that critically regulate Meth-induced neuronal remodeling and plasticity.