Understanding the molecular neurobiology of synaptic transmission in the brain is crucial for improving prevention and treatment for intellectual and developmental disorders. We are currently pursuing 2 projects that directly address this overall goal.
Project 1: In the human brain, the gain of information processing in neuronal circuits is tightly regulated at synapses. Plasticity of these synapses is the leading cellular model for learning and memory, and intellectual disability may involve changes that affect plasticity mechanisms of synapses. In contrast to the knowledge of mechanisms controlling the strength of postsynaptic signal reception, little is known about the molecular events during use-dependent modulation of presynaptic neurotransmitter release. In a nerve terminal, active zones form hot spots where synaptic vesicles fuse with the plasma membrane. Active zones are composed of a network of large multi-domain proteins, and they are required for the superb speed and precision of membrane trafficking during synaptic vesicle exocytosis. Our long-term goal is to dissect how the molecular composition of the active zone controls the properties of release, and how molecular adaptations at the active zone regulate the flow of information in a synaptic circuit. Diacylglycol (DAG) is a key second messenger in the brain. In a presynaptic nerve terminal, DAG induces a strong potentiation of neurotransmitter release, and it is also involved in remodeling of the nerve terminal and in activating presynaptically silent synapses. However, the molecular pathways downstream of DAG are incompletely understood. We thus performed a cell-based screen to search for novel presynaptic DAG targets. We identified the multi-domain active zone protein liprin-α as a target of DAG signaling. We hypothesize that DAG modulates presynaptic strength and plasticity by controlling release site composition and function through liprin-α. Our aims are (1) to dissect the molecular basis of the DAG/PKC/liprin-á signaling axis, and (2) to determine the roles of liprin-á in controlling presynaptic composition and strength.
Project 2: Many people in the United States with intellectual disability suffer disproportionately from substance abuse. Thus, for a better treatment of intellectual disability, it is critical to understand the molecular mechanisms and neural circuits involved in drug abuse. Although much progress was made in the definition of the underlying circuits, a better understanding of the neurobiology of drug addiction and the underlying synaptic changes is critical to progress in prevention and treatment. RIM proteins are central components of presynaptic active zones that orchestrate neurotransmitter release into a coherent process and mediate most if not all forms of presynaptic plasticity. To date very little is known about the participation of the presynaptic neurotransmitter release machinery in reward-based learning and addiction. The nucleus accumbens (NAc) is a key brain area in the mesolimbic dopamine system that is involved in reward and reward-based learning. The overall goal of this grant is to characterize the RIM-dependence of synaptic transmission in the NAc, and to assess RIM’s contribution to addiction-related behaviors. It is hypothesized that RIMs are necessary in the NAc for normal synaptic plasticity and cocaine-induced behaviors. The specific aims include: 1) Determining which RIM1 and/or 2 isoforms are expressed in the NAc, 2): examining the involvement of RIM1 and/or 2 in presynaptic short-term and long-term plasticity in the NAc, 3) determining the participation of RIM1 and/or 2 in cocaine-induced behavioral sensitization (BeS) and conditioned place preference (CPP), and 4) exploring whether RIMdependent presynaptic plasticity in the NAc is required for BeS and CPP.