Toxicant Induced dysregulation of parvalbumin interneuron development and function

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PROJECT SUMMARY/ABSTRACT Neurological diseases and psychiatric disorders account for ~28% of the global burden of disease. Our ability to prevent and treat these diseases and disorders is hindered by their complex, multifactorial etiologies. Our long- term goal is to help prevent neurological diseases and psychiatric disorders by using functional neuroimaging studies in zebrafish to understand the susceptibility of neural populations to toxicant exposures during critical periods of development. Disruptions in the balance of excitatory and inhibitory signaling contribute to a number of neurological diseases and psychiatric disorders including hyperactivity, autism, intellectual disabilities, schizophrenia, epilepsy, and Alzheimer’s Disease. A common theme connecting these diverse diseases and disorders is the disrupted development of parvalbumin (PV) interneurons. Our immediate goal is to gain insight into the molecular mechanisms mediating PV development and function and how these critical developmental processes are disrupted by toxicant exposure. To achieve this goal, we are developing a suite of genetic tools for visualizing the development, connectivity, and functioning of PV interneurons in vivo as well as tools for manipulating gene function specifically in PV interneurons. In addition, we are generating transgenic lines that allow us to visualize the assembly and functioning of excitatory circuitry in the context of our PV interneuron- specific manipulations. Our preliminary data indicate that dlx1, 5 and 6, known regulators of GABAergic and PV interneuron development, and multiple isoforms of PV, are downregulated following exposure to 2,3,7,8- Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a prototypical aryl hydrocarbon receptor (AHR) agonist. In Aim 1, we will utilize our genetic tool kit and functional neuroimaging to determine if exposure to different AHR agonists disrupts PV interneuron development and function. We will use cell-type specific genetic manipulations to activate AHR in PV interneurons and determine if AHR activation alters PV interneuron function, the assembly of excitatory circuits in the developing brain, and is sufficient to produce larval hyperactivity as well as deficits in adult learning and memory. Mammalian Sox9 and zebrafish sox9b are AHR targets and are also downregulated following exposure to a number of toxicants including mono-butyl phthalate, 6:2 chlorinated polyfluorinated ether sulfonate, valproic acid, and chlorpyrifos. Mammalian Sox9 marks radial progenitor cells (RGP), an important source of GABAergic interneurons. In Aim 2, we will determine whether zebrafish sox9b is an important transcriptional regulator of PV development, and if PV-interneuron specific loss of sox9b is sufficient to disrupt PV interneuron function and larval and adult behavior. In Aim 3, we will use photoconvertible indicators of neural activity to determine the differential effects of AHR agonist exposure on embryonic and larval brain function. Together, these studies will provide insight into the molecular mechanisms mediating PV interneuron development and toxicant-induced disruption of this critical cell-type. The proposed studies directly contribute to NIEHS’s Strategic Goal 1, parts c, d, & e.