Endothelial monoamine neurotransmitter metabolism at the blood-brain barrier - The term blood-brain barrier collectively describes the properties of central nervous system (CNS) vasculature which stringently regulate the movement of ions, molecules and cells between the blood and neural tissue. These properties protect the CNS from toxins, pathogens and CNS immune surveillance, and provide the neural tissue the necessary nutrients for proper function. The vascular endothelial cells of the CNS confer many of the properties of the blood-brain barrier, they form paracellular and transcellular barriers, and possess distinct transport properties that efflux potential toxins and deliver nutrients. Blood-brain barrier dysfunction is observed in a wide array of neurological diseases including epilepsy, multiple sclerosis, stroke, Parkinson’s Disease and Alzheimer’s Disease. The objective of this study is to identify novel genes that allow the blood-brain barrier to regulate the health and function of the CNS. We identified several genes highly enriched in CNS endothelial cells which are involved in the synthesis and degradation of monoamine neurotransmitters, dopamine and serotonin. Dopamine and serotonin are neuromodulators as they potentiate the firing rate of neurons. Outside of the synapse they function as traditional extracellular signaling molecules and hormones. Neural circuits incorporating dopamine and serotonin are involved in learning, reward, movement and mood, while dysfunction in monoaminergic systems are observed in a host of neurological diseases including Parkinson’s Disease, Alzheimer’s Disease, neuropathic pain and neuropsychiatric disorders. Metabolism of dopamine and serotonin by brain endothelial cells could be involved in the many processes and behaviors regulated by these monoamine neurotransmitters. To determine the functions of blood-brain barrier monoamine neurotransmitter metabolism, we generated conditional endothelial-specific knockouts of Ddc, MaoA and MaoB and examined the requirement of these genes in behavior and the brain levels of dopamine and serotonin. Our preliminary studies suggest that blood-brain barrier monoamine metabolism regulates the levels of monoamines in a behavior context-dependent manner. We will use the conditional endothelial-specific knockout mouse models to examine how the blood-brain barrier regulates behavior responses to sensory stimuli and determine the mechanisms by which blood-brain barrier monoamine metabolism regulates monoamine neurotransmitter levels and behavior. Lastly, we will examine if brain monoamine signaling is altered in endothelial-specific knockouts of blood-brain barrier monoamine metabolic genes.
