Dendritic Ca2+ Signals in Striatal Medium Spiny Neurons

The striatum is a key brain area that plays a central role in the initiation and execution of voluntary movements. Medium spiny neurons (MSNs) are the most common cell type in the striatum, and they give rise to the inhibitory projections that the striatum sends to other brain areas involved in motor coordination. Degeneration or perturbed function of MSNs occurs in several human movement disorders including Huntington's and Parkinson's as well as in certain psychiatric illnesses and drug addiction. As in most neurons, stimulus-evoked calcium entry into MSNs regulates many processes including neuronal excitability, circuit connectivity, and gene transcription. Recently, perturbed calcium handling has been identified in patients with Huntington's disease as well as in mouse models of the disease. Interestingly this defect is detectable before the appearance of any motor symptoms and may hint that altered calcium regulation directly leads to the neuronal dysfunction seen in later stages of the disease. Despite the existence of well-established techniques for the study of calcium handling in neurons, the properties of calcium signaling in dendrites of MSNs remain relatively unexplored. The proposed work will use a combination of 2-photon laser scanning microscopy, 2-photon laser uncaging, and whole-cell electrophysiology to analyze how MSNs integrate the activity of many synapses. Our study will examine how nonlinear interactions between the many types of voltage-gated ion channels found in MSNs and synaptic activity dictate both membrane depolarization and calcium signaling. A novel technique will be used to determine if the spatial arrangement of active synapses on the dendrite determines the net effect of synaptic activity on membrane depolarization. Furthermore we will examine whether these nonlinearities play a role in the induction of synaptic plasticity. Lastly, the effect of dopamine on synaptic integration and calcium handling will be examined. Ultimately, we hope to understand how the specialized electrophysiological and morphological properties of MSNs influence striatal function and how perturbation of these processes contributes to human disease.