Cell, Vol. 72/Neuron,Vol. 10 (Suppl.), 123-137, January, 1993, Copyright© 1993 by Cell Press Neuronal Differentiation Factors/Cytokines and Synaptic Plasticity Paul H. Patterson* and Hiroyuki Nawat *Biology Division California Institute of Technology Pasadena, California 91125 tCold Spring Harbor Laboratory Cold Spring Harbor, New York 11724 Introduction As in the hematopoietic system, the enormous variety of phenotypes in the nervous system arises, in part, through the action of instructive differentiation signals. Such sig- nals include secreted and cell-bound proteins as well as steroid hormones. Since these agents have broad effects on cell proliferation and gene expression in many different tissues, the term cytokines is being adopted for the pro- teins. The original meaning of that term refers to cell move- ment, an activity that the present proteins could turn out to share (Cohen et al., 1974; see also Nathan and Sporn, 1991). Our focus here is on the regulation of neuronal gene expression by these factors, particularly the genes that code for neuropeptides and the enzymes that synthesize neurotransmitters, because these are the molecules di- rectly responsible for transmission of information at syn- apses. We highlight parallels between the control of phe- notypic expression in the nervous and hematopoietic systems and between the cytokines involved in the im- mune response and the response of the nervous system to injury. Attention is also drawn to a potential role for cytokines in synaptic plasticity. For instance, changes in transmission at particular synapses that underlie distinc- tive behavioral states are often associated with alterations in the expression of the neurotransmitters and neuropep- tides employed at those synapses. Such changes in ex- pression can also occur during daily or monthly physiologi- cal changes in the body. Moreover, certain paradigms widely used to study the phenomena of learning and mem- ory have, in a few cases, suggested an involvement of cytokines in the plasticity of synaptic transmission. Regulation of Neuronal Gene Expression by Cytokines Released from Their Target Cells-Retrograde Influences The classical actions of cytokines in the nervous system are as retrograde, or target-derived, signals (Figure 1). Neuronal targets such as muscles use these factors to regulate the neurons that innervate them. The discovery of such factors was based on their involvement in neuronal cell death. In many parts of the nervous system, 50% of the neurons produced during embryogenesis die during subsequent development, and the target tissues that neu- rons innervate can play a large role in controlling how many neuronssurvive. This survival effect of targets is mediated in part by growth or trophic factors, the first iso- lated being nerve growth factor (NGF). (See Table 1 for a list of all the abbreviations used in this review.) The family of NG F-related su rvival factors is now composed of at least five members (the neurotrophins; Thoenen, 1991; Altin and Bradshaw, 1992). These proteins are not only required for survival,'but they enhance neuronal growth in a dose- dependent manner (Chun and Patterson, 1977). Growth, in this case, refers to the size of a neuron and its processes rather than mitosis, although NGF can induce both growth and mitosis in the same cells (Stemple et al., 1988). In addition to neuronal growth, target tissues can also control the phenotype of the neurons that innervate them. Phenotypic traits that are regulated in a qualitative fashion by targets in vivo include the neurotransmitters and neuro- peptides produced (Landis, 1990) and the synapses the neuron receives on its dendrites. That is, targets that the axons of a neuron encounter in the periphery can influence the connections that other cells make on the dendrites of that neuron in the central nervous system (or CNS) (re- viewed in French and Kristan, 1992; Patterson and Landis, 1992). Such qualitative alterations in phenotype can be regulated by the neuronal differentiation factors, whose effects can be distinguished from the classical NGF sur- vival and growth activities. Differentiation factors charac- teristically alter neuronal gene expression and phenotype Target Presynaptic ~ /HORMONES cellf ~ terminal / ' Schwann cells ANTEROGRADE ~Hemato[~ietic R~'ROG~DE V cells Figure 1. Influences on Neuronal Gene Ex- pression The diagramsummarizes the fivetypesof infl u- enceson neuronal geneexpression: hormones in the circulation, signalsfrom gila and cells of the immunesystem, as well as factors passed between neuronsin the forward (anterograde; neuronto target cells)and reverse(retrograde; target cell to its innervation) directions.