Neuronal secretory pathway

A major focus of the lab concerns the long-lasting changes at synapses caused by drugs of abuse that remodel neural circuits and cause addiction. We have recently uncovered novel effects of nicotine and synaptic activity on the reorganization of elements of the neuronal secretory pathway. Nicotine exposure and membrane excitation in either neurons or non-neuronal cells led to dissolution of the Golgi’s compact, centralized appearance and to the formation of scattered Golgi elements localized adjacent to ER exit sites and endosomes (see model). The disseminated Golgi elements (Golgi satellites) are mobile in dendrites and axons, especially in response to changes in activity or nicotine treatment, and in vivo exposure of mice to nicotine increases the number of Golgi satellites in the dopaminergic axonal terminals of neurons in the mid-brain reward ventral tegmental area (VTA). We have identified several cargo proteins that traffic through these specialized organelles and undergo dynamic alterations in glycosylation, including the α4β2R-subtype of the nicotinic acetylcholine receptor family (nAChRs). This is an intriguing finding, since prolonged nicotine exposure increases high-affinity α4β2R binding sites in the brain, in a process termed “upregulation” that is linked to craving and withdrawal in nicotine addiction.

Current projects utilize rodent cellular models and cellular imaging approaches to characterize the signaling mechanisms that lead to the formation and regulation of these Golgi satellite structures. This has important implications for increasing our understanding of neuronal cell biology, elucidating nicotine’s addictive properties, and in the design of more efficacious smoking cessation agents. We are also investigating whether other kinds of neuronal activity and/or forms of synaptic plasticity are similarly influenced by changes in Golgi satellite morphology, trafficking, and function.