The Role of Interleukin-1, Interleukin-6, and Glia in Inducing Growth of Neuronal Terminal Arbors in Mice

Abstract

After injury to the substantia nigra pars compacta (SNpc), remaining neurons sprout to ensure normal dopamine delivery to the striatum. The consequent striatal reinnervation is highly regulated, with remaining cells sprouting so that density of dopamine terminals returns to normal. Sprouting as a result of injury is accompanied by a strong glial response; however, it is difficult to know whether this response is as a result of the injury or whether it is aiding in the sprouting. The two cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6) are important modulators of the glia response. This study demonstrates their role in regulating the sprouting of dopaminergic neurons and the associated glia response as a means to examine the role of glia in sprouting. Sprouting was induced by 6-hydroxydopamine lesions of the SNpc and by haloperidol treatment (in the absence of injury). In wild-type animals, sprouting in association with microglial and astrocyte proliferation followed partial lesions of the SNpc and haloperidol treatment. Neither treatment evoked sprouting or glia proliferation in the type I IL-1 receptor-deficient mice, whereas in IL-6-deficient mice, both treatments resulted in glial proliferation but not sprouting. We conclude that IL-1 plays a role in modulating glia proliferation and thereby guidance and trophic factors for new fibers, whereas IL-6 may be important in triggering the outgrowth of new fibers. This study demonstrates that these cytokines play an important role in plasticity and regeneration that is separate from the inflammatory response associated with brain injury.

Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

“…The up-regulated astrogliosis and microgliosis suggest a degree of cortical remodeling, and we hypothesize there may be compensatory neurogenesis as seen in other injury models (47) and selection of cells that do not express Drd1a. It is also possible that the glial response seen in the cortex is a function of remodeling of neuronal processes (49,50). Because cortical volume does not change (on serial MRI analysis), whereas striatal volume decreases in concert with the emergence of pivotal aspects of the HD phenotype, such as hindlimb clasping, we suggest that striatal rather than primary cortical pathology explains the motor abnormalities in the model.…”

Vesicle-Mediated Transport and Release of CCL21 in Endangered Neurons: A Possible Explanation for Microglia Activation Remote from a Primary Lesion

“…Furthermore, activated microglia have been shown to be instrumental for long-term changes in response to brain lesions (Banati, 2002a,b;Beattie et al, 2002;Parish et al, 2002;Monje et al, 2003).…”

“…Recent results show a significant impact of activated microglia on these lesion-induced long-term changes (Banati, 2002a;Beattie et al, 2002;Parish et al, 2002;Monje et al, 2003). Activated microglia can either inhibit neurogenesis (Monje et al, 2003) or support neuronal sprouting (Parish et al, 2002), showing that microglia activation is a double-edged sword. It is thus of particular interest to understand how microglia activity is controlled.…”

GDNF and PD: Less Common Points of View

“…These data clearly show that activated microglia and macrophages induce dopaminergic sprouting through synthesis of neurotrophic factors. Interleukin-1 (IL-1) is also involved in dopaminergic sprouting since IL-1 receptor knockout mice do not show neuronal sprouting after a 6-OHDA lesion (Parish et al, 2002). IL-1, produced by reactive microglia and macrophages, induces astrogliosis.…”

“…IL-1, produced by reactive microglia and macrophages, induces astrogliosis. Therefore, activated microglia and macrophages appear to stimulate dopaminergic sprouting both directly, by the secretion of neurotrophic factors, and indirectly by the secretion of IL-1 and the stimulation of reactive astrocytosis (Ho & Blum, 1998;Parish et al, 2002). Furthermore, a protective role of microglia in the dopaminergic system was also suggested by results showing that striatal injection of 6-OHDA increases the number of neuron/glial 2 (NG2) cells coexpressing the microglia marker Iba1 and GDNF, both in the striatum and substantia nigra.…”