Dopaminergic regulation of dendritic spine function and plasticity in prefrontal cortex

Project Summary/Abstract Perturbation of spine function or development produces profound behavioral and cognitive dysfunction and remains a critical component to neurodevelopmental and neurodegenerative synaptopathies such as schizophrenia. While dendritic spines mediate glutamatergic signaling, recent evidence suggests that dopamine modulates dendritic spine plasticity in in vitro reduced model systems. The central goal of this project is to identify the role of dopamine on dendritic spine plasticity in vivo. My main hypothesis is that local dopaminergic signaling mediates the emergence, function, and pruning of dendritic spines. In Aim-1 I will use holographic imaging of functional responses of dendritic spines to synaptic inputs in vivo. In Aim-2, I will use holographic optogenetic stimulation of dopaminergic neuron terminals and caged dopamine to investigate the control of dendritic spine voltage dynamics via dopaminergic signaling. Finally, in Aim-3 I will perform experiments using both glutamate and dopaminergic signaling to study their roles in dendritic spine dynamics in mouse models of schizophrenia. I will use voltage imaging with a novel genetically encoded voltage indicator targeted to dendritic spines (spASAP). To measure the structural (morphological differences) and functional (voltage fluctuation) responses of spines, I will perform these aims in layer 5 of prelimbic area of mouse prefrontal cortex, an area where dopaminergic neurons project and implicated in schizophrenia, as well one that exhibits dysregulation of spine number and morphology distribution but without significant functional characterization. My proposed studies will greatly expand the understanding how relationships to voltage fluctuations are altered by key mechanisms related to dopaminergic modulation of dendritic spine plasticity, and how dendritic spine plasticity are dysregulated in diseases such as schizophrenia.