Laboratory of Nicole Calakos, M.D., Ph.D.MainLab Personnel
Molecular Mechanisms of Synaptic Plasticity

The stuff memories are made of…

We all know that as part of our daily lives we are constantly interacting with our environment - learning, adapting, establishing new memories and habits, and alas, forgetting as well. At the cellular level, these processes can be encoded by changes in the strength of synaptic transmission between neurons. The process by which neuronal connections change in response to experience is known as “synaptic plasticity” and this process is a major interest of our laboratory. Our goals are to understand the molecular mechanisms for synaptic plasticity and identify when these processes have gone awry in neurological diseases. In doing so, we will establish the necessary framework to then target these processes for therapeutic interventions; potentially identifying novel and improved treatment options. Currently, the lab is pursuing these questions in two areas.

The first area is focused on the mechanisms and functional significance of synaptic plasticity at the corticostriatal synapse. This synapse is a key entry point for cortical information into the basal ganglia circuitry. The basal ganglia are involved in a wide variety of behaviors because they are critical for the acquisition and subsequent decision to execute motor “programs.” Disorders in this process have wide ranging manifestations from Parkinson’s disease to drug addiction. One important aspect of basal ganglia circuit function is the balance of synaptic transmission between the so called “direct” or striatonigral and “indirect” or striatopallidal pathways. Imbalances between these pathways have been implicated in diseases such as Parkinson’s and Huntington’s and may potentially contribute to others. We recently created a novel platform that makes it possible for the first time to study the function of striatal medium spiny neurons in each of these pathways simultaneously in living tissue (Shuen et al., 2008). Using this platform, we are defining functional differences between these two types of medium spiny neurons and establishing whether they are differentially involved in disease processes. Recent work has focused on synaptic dysfunction due to deletion of the postsynaptic scaffold protein, SAPAP3 and its relation to Obsessive Compulsive Disorder (OCD)-like behaviors (Welch et al., 2007). Other studies concern corticostriatal transmission and the pathophysiology of dystonic disorders.

The second major area of interest is in understanding the molecular basis and function of presynaptic forms of plasticity. Most recently, we have been studying RIMs, a family of large scaffold proteins that localize to the presynaptic active zone. Studies of RIM1 knockout mice have demonstrated roles for RIM in basal neurotransmission, short term plasticity and long term plasticity (Calakos et al., 2004; Castillo et al., 2002, Schoch et al., 2002). These mice also exhibit learning disabilities in behavioral paradigms (Powell et al., 2004). RIMs are predicted to integrate the activities of a wide variety of presynaptic proteins by virtue of their multitude of protein-protein interactions. Through the study of the RIM family of proteins, we hope to understand the molecular mechanisms of presynaptic plasticity, the functional significance of this form of plasticity for the organism as a whole, and lastly, how to target RIM or its interacting proteins for therapeutic interventions in candidate neurological diseases.

To tackle both of these questions, we take advantage of cellular electrophysiological recording techniques to directly evaluate synaptic function. Currently, we use acute brain slices and cultured neuron platforms combined with genetic and viral technologies that enable us to molecularly manipulate the synapses we are studying. Our synaptic physiology studies are further complemented by a variety of genetic, biochemical and imaging technologies. As we uncover the molecular and cellular basis of synaptic plasticity, we continually look for opportunities, often collaborative, to extend and test our findings at the circuit and behavioral levels.

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©2010 Center for Translational Neuroscience
Duke University Medical Center
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