Critical roles for the netrin receptor deleted in colorectal cancer in dopaminergic neuronal precursor migration, axon guidance, and axon arborization.

DCC (deleted in colorectal cancer), a receptor for the axon guidance cue netrin-1, is highly expressed by mesencephalic dopaminergic (DA) neurons during development; however, the contribution of DCC to DA development remains largely uncharacterized. DA neurons in ventral mesencephalic nuclei also express UNC5 homologue netrin receptors from late embryogenesis to adulthood, raising the possibility that DA axons could be attracted or repelled by netrins. Examining newborn dcc null mice, we report that loss of DCC function results in profound alterations of DA circuitry, including DA progenitor cell migration defects, reduced numbers of DA cells in midbrain nuclei, an anomalous DA ventral commissure, malformed DA innervation of the ventral striatum, and reduced DA innervation of the cerebral cortex. Caspase-3 activation was detected in inappropriately localized DA cells, consistent with apoptosis contributing to reduced cell numbers. Dcc heterozygous mice express reduced levels of DCC protein. Although less severely disrupted than dcc nulls, newborn and adult dcc heterozygotes also have fewer DA neurons in ventral mesenscephalic nuclei. Despite the reduced numbers of DA neurons, newborn dcc heterozygotes and nulls exhibit similar DA innervation density as wild-type littermates in the nucleus accumbens core, and adult dcc heterozygotes exhibit increased DA innervation in medial prefrontal cortex. A trend towards increased innervation of medial prefrontal cortex was detected in newborn dcc heterozygotes, but did not reach statistical significance, suggesting that the increase in adult heterozygotes results from enhanced DA arborization during postnatal development. Consistent with the hypothesis that DCC regulates DA axonal projections, disrupting DCC function in culture inhibits netrin-1 induced DA axon extension and axon branching. Furthermore, disrupting DCC function in isolated DA neurons grown as micro-island cultures reduces the number of autaptic synapses per cell. We conclude that DCC regulates appropriate precursor cell migration, axon guidance, and terminal arborization by DA neurons.

The anti-inflammatory cytokine, interleukin (IL)-10, blocks the inhibitory effect of IL-1 beta on long term potentiation. A role for JNK.

Several effects of the proinflammatory cytokine, interleukin-1 beta (IL-1 beta), have been described in the central nervous system, and one area of the brain where marked changes have been reported is the hippocampus. Among these changes are an IL-1 beta-induced inhibition of long term potentiation (LTP) in perforant path-granule cell synapses and an attenuation of glutamate release in synaptosomes prepared from the hippocampus. Evidence suggests that, at least in circulating cells, the anti-inflammatory cytokine, IL-10, antagonizes certain effects of IL-1. We investigated the effect of IL-10 on IL-1 beta-induced inhibition of LTP and glutamate release. The evidence presented indicates that IL-1 beta stimulates the stress-activated protein kinase, c-Jun-activated protein kinase (JNK), and IL-1 receptor-associated kinase, which may explain its inhibitory effect on release and LTP, and that IL-10 reversed the IL-1 beta-induced stimulation of JNK activity and inhibition of release and LTP. We observed that IL-10 abrogated the stimulatory effect of IL-1 beta on superoxide dismutase activity and reactive oxygen species production, whereas the H(2)O(2)-induced inhibition of LTP was also blocked by IL-10. We present evidence that suggests that the action of IL-10 may be mediated by its ability to induce shedding of the IL-1 type I receptor.

Evidence that interleukin-1beta and reactive oxygen species production play a pivotal role in stress-induced impairment of LTP in the rat dentate gyrus.

Long-term potentiation (LTP) in both area CA1 and the dentate gyrus is attenuated by stress and the evidence is consistent with the view that this is a consequence of increased activation of glucocorticoid receptors, in the hippocampus, following the stress-induced increase in circulating corticosterone. It has been shown that expression of the pro-inflammatory cytokine, interleukin-1beta (IL-1beta), is increased in hippocampus in response to stress; this finding together with the observation that IL-1beta exerts an inhibitory effect on LTP, suggests that IL-1beta may play a key role in mediating this inhibitory effect of stress on LTP. In this study, we explore this possibility and report that stress is also associated with increased reactive oxygen species production. The evidence presented supports the view that this is secondary to the stress-induced increase in IL-1beta concentration, as IL-1beta increased activity of superoxide dismutase and increased reactive oxygen species accumulation in hippocampus in vitro. We report that the inhibitory effect of stress on LTP is mimicked by H2O2, which increases reactive oxygen species accumulation, and by IL-1beta, the effect of which is overcome by the antioxidant, phenylarsine oxide. The hypothesis that the stress-induced increase in reactive oxygen species production may underlie the suppression of LTP is further supported by the finding that the effect of stress is abrogated by dietary manipulation with antioxidant vitamins E and C.

The inhibitory effect of interleukin-1beta on long-term potentiation is coupled with increased activity of stress-activated protein kinases.

Long-term potentiation (LTP) in perforant path-granule cell synapses is decreased in aged rats, stressed rats, and rats injected intracerebroventricularly with the proinflammatory cytokine interleukin-1beta (IL-1beta). One factor that is common to these experimental conditions is an increase in the concentration of IL-1beta in the dentate gyrus, suggesting a causal relationship between the compromise in LTP and increased IL-1beta concentration. In this study, we have investigated the downstream consequences of an increase in IL-1beta concentration and report that the reduced LTP in rats injected intracerebroventricularly with IL-1beta was accompanied by a decrease in KCl-stimulated glutamate release in synaptosomes prepared from dentate gyrus, although unstimulated glutamate release was increased. These changes were paralleled by increased activity of the stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. Intracerebroventricular injection of IL-1beta increased reactive oxygen species production in hippocampal tissue, whereas IL-1beta and H(2)O(2) increased activities of both JNK and p38 in vitro. Dietary manipulation with antioxidant vitamins E and C blocked the increase in reactive oxygen species production, the stimulation of JNK and p38 activity, the attenuation of glutamate release, and the IL-1beta-induced inhibitory of LTP. We propose that IL-1beta stimulates activity of stress-activated kinases, which in turn may inhibit glutamate release and result in compromised LTP and that these actions are a consequence of increased production of reactive oxygen species.

Lipopolysaccharide inhibits long term potentiation in the rat dentate gyrus by activating caspase-1.

Lipopolysaccharide, a component of the cell wall of Gram-negative bacteria, may be responsible for at least some of the pathophysiological sequelae of bacterial infections, probably by inducing an increase in interleukin-1beta (IL-1beta) concentration. We report that intraperitoneal injection of lipopolysaccharide increased hippocampal caspase-1 activity and IL-1beta concentration; these changes were associated with increased activity of the stress-activated kinase c-Jun NH(2)-terminal kinase, decreased glutamate release, and impaired long term potentiation. The degenerative changes in hippocampus and entorhinal cortical neurones were consistent with apoptosis because translocation of cytochrome c and poly(ADP-ribose) polymerase cleavage were increased. Inhibition of caspase-1 blocked these changes, suggesting that IL-1beta mediated the lipopolysaccharide-induced changes.

Age-related impairment in LTP is accompanied by enhanced activity of stress-activated protein kinases: analysis of underlying mechanisms.

The age-related impairment in long-term potentiation in the rat dentate gyrus is coupled with an increase in the proinflammatory cytokine, interleukin-1beta (IL-1beta). It is possible that this increase in IL-1beta might be a consequence of the age-related increase in reactive oxygen species production in hippocampal tissue. In this study we set out to identify the underlying cause of the age-related increase in reactive oxygen species production and to establish whether any consequences of such a change might impact on the ability of aged rats to sustain long-term potentiation (LTP). We report that there was an age-related increase in the activity of superoxide dismutase but no parallel increases in activities of glutathione peroxidase or catalase, while age-related decreases in the concentration of the scavengers, vitamins E and C and glutathione were also observed. We propose that these compromises in antioxidative strategies may result in an increase in reactive oxygen species production. The data described indicate that IL-1beta and H2O2 increase the activity of two stress-activated mitogen-activated protein kinases, c-Jun NH2-terminal kinase (JNK) and p38 in vitro, while age-related increases in both kinases were observed. We propose that the endogenous increase in these parameters which occurs with age induces the increase in activity of the stress-activated kinases, which in turn impacts on the ability of the aged rat to sustain LTP.

Neuropeptide Y inhibits glutamate release and long-term potentiation in rat dentate gyrus.

The effect of intracerebroventricular injection of neuropeptide Y (NPY) was assessed on LTP in dentate gyrus. We report that NPY attenuated LTP and inhibited KCl-induced glutamate release in synaptosomes prepared from dentate gyrus. Activity of the stress-activated kinase, c-Jun NH2-terminal kinase (JNK) in synaptosomes was increased by incubation with NPY or following intracerebroventricular injection. Activation of JNK might underlie the inhibitory effect of NPY on LTP.