Cytokines in Synaptic Function

Cytokines perform an extensive range of overlapping functions both outside and inside the central nervous system (CNS). Some of the roles for cytokines include immunologic, inflammatory, and hematopoietic functions, as well as the regulation of neuron differentiation, survival, and plasticity, and in particular the regulation of neuron synaptic function. The transmission of signals by neurons in the CNS involves multiple interactions between the neuron and numerous accessory cells. These interactions are mediated by various factors, including short-acting soluble cytokines. These polypeptides impart profound effects over synaptic responsiveness. Although cytokines have diverse actions, they all share some common properties that dictate their involvement in the nervous system. Originally characterized as either pro- or anti-inflammatory mediators primarily produced by cells of the immune system, it is now apparent that cytokines serve major roles in the nervous system. These roles involve preserving neuron homeostasis, not necessarily in the face of an ensuing inflammatory or immune response. Appropriately, the term cytokine has now been adopted as a general umbrella for many types of secreted proteins that mediate diverse biological responses including synaptic responsiveness. Belonging to the cytokine family are (1) interleukins, (2) interferons, (3) chemokines, and (4) tumor necrosis factors. For the purpose of this chapter, each of these family members will be discussed with relevance to their roles in synaptic function. Particular emphasis will be placed on the group including tumor necrosis factor-α (TNF-α). The synapse is the location for the delivery of neurotransmitter from neuron to neuron. However, our concepts of synaptic transmission are in flux, requiring constant reevaluation. With the blossoming of our knowledge of cytokine involvement in synaptic function, our concepts are continually evolving. Most synapses rely on a chemical intermediary. Moreover, the chemical synapse is characterized by great flexibility and, therefore, adapts to environmental cues. This flexibility of the synapse depends on modifications by mediators such as cytokines. It is now obvious that many cytokines are used constitutively by cells of the CNS as signaling molecules involved in intercellular communication. Therefore, this interaction of cytokines at the synapse allows flexibility in synaptic function and subsequent behavior. This leads to a complex processing of information that is necessary to modify neuronal circuits in the multitude of processes governed by the nervous system. The role of cytokines in brain signaling has, therefore, gained recent recognition as emphasized in this presentation. Neurons are the fundamental building blocks of the CNS that transmit information at the synapse. Consequently, control over synaptic function would have significant impact on the brain and spinal cord. As with any control system, numerous mechanisms interact with each other to tightly maintain synaptic regulation of neurotransmitter release. Given the complexity of synaptic regulation that exists when accounting for the tasks performed by the brain, it is not surprising that many mediators, including pleiotropic cytokines, play an integral role in this regulation. By increasing our understanding of the relationship between cytokines and synaptic functions, powerful new classes of drugs that act in the CNS will be developed. Neurological disorders are becoming increasingly common due to the considerable growth of an aging population. These disorders are costly and can arise from many diseases (e.g., AIDS). The design of drugs targeted at cytokines and/or their effects at the synapse, we believe, will improve brain function and thereby benefit individuals experiencing disorders of the CNS.