Formation, Function, and Stability of Neuronal Connections
We have identified a signaling cascade involving integrin adhesion receptors, Arg, p190RhoGAP, and several additional molecules that is critical for synapse and dendrite stabilization in the postnatal mouse brain. A major goal is to identify ligands that act upstream in this pathway to trigger synapse and dendrite stability. We envision manipulation of this molecule could be used therapeutically to stabilize synapses and dendrites to treat diseases (e.g.schizophrenia, autism, neurodegeneration) typified by synapse loss.
We have recently developed long-term hippocampal neuron cultures as an important tool to probe the biochemical mechanisms controlling synapse and dendrite stability and this approach has already yielded important new mechanistic insights. We hope to use this system to more widely probe the contributions of neurological disease-related genes to synapse and dendrite stability in vivo.
Synapse and dendrite loss in the human prefrontal cortex is associated with impulsivity and increased susceptibility to psychostimulant abuse. arg–/– mice undergo significant cortical synapse and dendrite loss during late adolescence, making them an ideal model system to understand how these changes affect these behaviors. In collaboration with Shannon Gourley and Jane Taylor (Yale Molecular Psychiatry), we find that arg–/– mice exhibit increased impulsivity and hypersensitivity to cocaine. To gain insights into genetic susceptibility to drug abuse, we are determining how genetic lesions in other Arg signaling pathway components affect these behaviors in mice.