The central question of the parent award is to understand the relationship between cortico-striatal synaptic function and pathological behaviors. The initial step toward this was to understand the striatal synaptic defects created by deletion of the SAPAP3 gene in mice, a manipulation that produced a behavioral constellation (excessive grooming, anxiety-like behaviors, and fluoxetine responsiveness) suggesting relevance to human diseases within the spectrum of Obsessive Compulsive disorders. The central role of the striatum in these behavioral manifestations has been demonstrated by rescuing the behaviors with in vivo viral-mediated SAPAP3 expression delivered exclusively to the striatum. Because SAPAPs have only been detected in excitatory synapses, the culprits of pathological striatal synaptic function were further narrowed down. Using whole-cell, voltage-clamp electrophysiological techniques, we have identified excitatory synaptic defects in medium spiny neurons projecting to the direct and indirect pathways and of synapses in the corticostriatal and thalamostriatal circuits. In order to ultimately understand how synaptic defects produce behavioral abnormalities, an understanding of how the defined synaptic defects alter activity at the circuit level is of paramount importance. We propose to supplement our additional proposal with experiments that take this next step by investigating the integrated effects of SAPAP3 dysfunction on striatal circuitry using novel genetic tools and imaging advances that were not available at the initial submission of this award. Specifically we propose to evaluate neuronal firing patterns in the local circuitry of the striatum by combining the use of BAC transgenic mice expressing fluorescent markers to identify striatal cell types, functional imaging techniques to detect neuronal spiking, conventional and optogenetic stimulation to activate afferent axons in distinct patterns, and advanced imaging techniques to image a large population of neurons in acute brain slices simultaneously. The combined advantages of these techniques will allow us to identify differences in striatal circuit activity in SAPAP3 KO mice in a way that overcomes the current inadequacies of addressing this question using either conventional acute slice electrophysiology or in vivo recordings. The combined result of our investigations of isolated subthreshold excitatory synaptic defects and the net impact on striatal circuit activity will enrich our understanding of the relationship between synaptic function and behavior and enable the design of rationale therapies that may target either focal synaptic mechanisms or their circuit perturbations.
Pathological behaviors due to SAPAP3 dysfunction may have relevance for human disorders involving compulsive behaviors such as those within the spectrum of Obsessive Compulsive disorders. In this mouse model, striatal dysfunction is central to the expression of the behaviors. As such, by understanding how dysfunction of striatal synaptic transmission can lead to pathological behavior, our findings also relate to the broader range of human disorders involving striatal dysfunction, such as addiction, tics/Tourette's, Parkinson's, Huntington's and dystonia.
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