Mast cells are multifunctional bone marrowderived cells found in mucosal and connective tissues and in the nervous system, where they play-important roles in tissue inflammation and in neuroimmune interactions. Very

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The neurotrophins are a family of closely related proteins that were first identified as survival factors for sympathetic and sensory neurons and have since been shown to control a number of aspects of survival, development, and function of neurons in both the central and peripheral nervous systems. Limiting quantities of neurotrophins during development control the numbers of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. Biological effects of each of the four mammalian neurotrophins are mediated through activation of one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB, and TrkC). In addition, all neurotrophins activate the p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily. Neurotrophin engagement of Trk receptors leads to activation of Ras, phosphatidylinositol 3-kinase, phospholipase C-γ1, and signaling pathways controlled through these proteins, including the mitogen-activated protein kinases. Neurotrophin availability is required into adulthood, where they control synaptic function and plasticity and sustain neuronal cell survival, morphology, and differentiation. This chapter will provide an overview of neurotrophin biology, their receptors, and signaling pathways.

Purine nucleotides are well established as extracellular signaling molecules. P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. Several P2X receptor subtypes, including P2X(7), have the unusual property of changing their ion selectivity during prolonged exposure to ATP, which results in progressive dilation of the channel pore and the development of permeability to molecules as large as 900 Da. The P2X(7) receptor was originally described in cells of hematopoietic origin, including macrophages, microglia, and certain lymphocytes, and mediates the influx of Ca(2+) and Na(+) ions, as well as the release of proinflammatory cytokines. P2X(7) receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1beta, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X(7) receptors provides an inflammatory stimulus, and P2X(7) receptor-deficient mice have substantially attenuated inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X(7) receptor activity, by regulating the release of proinflammatory cytokines, may be involved in the pathophysiology of depression. The P2X(7) receptor may thus represent a critical communication link between the nervous and immune systems, while providing a target for therapeutic exploitation. This review discusses the current biology and cellular signaling pathways of P2X(7) receptor function, as well as insights into the role for this receptor in neurological/psychiatric diseases, outstanding questions, and the therapeutic potential of P2X(7) receptor antagonism.

Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system (“neuroinflammation”), especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia) and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell—cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenous mechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation.