Role of the chemokine receptor CX3CR1 in neuronal transmission and brain development and its potential association with Attention Deficit/Hyperactivity Disorder (ADHD)

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In addition to its functions in the immune system, the chemokine CX3CL1 (fractalkine) modulates microglia activation, neuronal development and neurotransmission in the central nervous system (CNS). CX3CL1 is tethered to the cell membrane of neurons and expressed in the CNS at higher levels than in the periphery. CX3CR1, the corresponding receptor, is mainly expressed on microglia cells, modulating neuron-microglia communication. Behavioral tests showed that CX3CR1(-/-) mice have impaired ability to focus on a specific task and may represent a new animal model for attention deficit/hyperactivity disorder (ADHD). We propose that CX3CR1 may influence neurotransmitter release and the development of brain areas involved in the regulation of attention. We will investigate brain volume and development in CX3CR1(-/-) mice by magnetic resonance imaging. With brain slices and primary neuron cultures from CX3CR1(-/-)- and wild-type mice we will study electrophysiology as well as neurotransmitter uptake and release. Moreover, we will elucidate the role of microglia in brain development by immunohistochemical methods in CX3CR1(-/-)- and wild-type mice. The goal of the project is to characterize a novel animal model for ADHD and to develop new starting points for the investigation of the pathogenesis of human ADHD.