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Calakos Lab

Photo of Nicole Calakos

Nicole Calakos

Office: Bryan Research Building 201E
Phone: 919-684-2423
Email: nicole.calakos@duke.edu

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 for better or for worse, 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 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 in the striatal circuitry of the basal ganglia. The striatum is a key entry point for cortical information into the basal ganglia. The basal ganglia are involved in a wide variety of behaviors because they are critical for our movement, including the learning of motor routines and when to call them into action. Disorders in this process have wide ranging manifestations from Parkinson’s disease to OCD. One important aspect of basal ganglia circuit function is the balance of activity between the “direct” (striatonigral) and “indirect” (striatopallidal) pathways. Imbalance between these pathways has been implicated in diseases such as Parkinson’s and Huntington’s and is likely to contribute to others. 

To get a better view of how pathway balance may be affected, our lab developed 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; Ade et al., 2011, O’Hare and Ade et al., 2016). Using this platform, we are defining functional differences between these two types of medium spiny neurons and their role in normal adaptive plasticity and disease processes.

In habit, we have identified circuit predictors of behavior. These include some classic expectations for mechanisms of plasticity such as increased firing activity, but also some surprises, like finding shifts in the timing of firing between these two cell types (O’Hare and Ade et al., 2016).

In disease models, we examine the synaptic and circuit basis for repetitive, compulsive behaviors by studying the synaptic role of SAPAP3 and its relation to Obsessive Compulsive Disorder (OCD)-like behaviors in mice (Welch et al., 2007; Chen et al., 2011; Wan et al., 2011). One of the major outcomes of this work has been identifying a central role for striatal group 1 metabotropic glutamate receptor dysregulation (Chen et al., 2011; Wan et al., 2011). Other studies examine the role of corticostriatal transmission in the pathophysiology of movement disorders such as dystonia and Tourette’s Syndrome.

The second area of interest is in understanding the molecular basis and function of presynaptic forms of plasticity. RIMs are a family of large scaffold proteins that localize to the presynaptic active zone. Studies of RIM1α knockout mice have demonstrated roles for RIM in basal neurotransmission, short term plasticity and long term plasticity.

Ying Yang, while a graduate student in the lab, created an approach to test the molecular mechanisms of presynaptic plasticity at hippocampal mossy fiber synapses using in vivo viral manipulation of gene expression (Yang and Calakos, 2010). Using this approach, she found that the vesicle priming protein, Munc13, is also required for presynaptic LTP at these synapses, via an interaction with RIM that is known to regulate the amount of vesicle priming (Yang and Calakos, 2011). 

These results advance our understanding of both the molecular and cellular mechanisms underlying presynaptic long-term plasticity. In future work, we hope to define the behavioral significance of this form of plasticity and identify how to target RIM or its interacting proteins for therapeutic interventions in candidate neurological diseases.

To tackle all of these research questions, we use cellular electrophysiological recording techniques and advanced imaging methods to directly evaluate neuronal activity. As we uncover the molecular and cellular basis of synaptic plasticity, we test the implications of our findings at the circuit and behavioral levels. We take advantage of a range of molecular genetic and imaging technologies to do this. Our research is also greatly influenced by the rich collaborations we have with colleagues at Duke and beyond.