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Cereblon is implicated in mild mental retardation and proved to bind to a teratogenic hypnotic, thalidomide. Here, we determined cereblon mRNA distributions in adult mouse brain. Almost all neurons expressed cereblon mRNA with various intensities whereas the signals in astrocytes and oligodendrocytes were modest or negligible. Intense mRNA signals were found in the hippocampus and cerebellum, especially in hippocampal pyramidal cells and Purkinje cells. Higher levels of cereblon mRNA were also detected in serotonergic and noradrenergic neurons in raphe nuclei and locus ceruleus, respectively. These observations indicate novel biological roles of cereblon in neuronal physiology and thalidomide pharmacology.

The exact role of cyclooxygenase-2 (COX-2) in neurodegeneration of retinal ganglion cells (RGCs) in vivo following ischemia-reperfusion injury of the retina was unknown. We made transgenic mice in which the Thy-1.2 promoter drives the expression of EGFP cDNA (Thy-1-EGFP) in RGCs to monitor RGC survival and death in retinal whole mount preparations and in live animals. We show that celecoxib, a selective COX-2 inhibitor, blocks RGC death after ischemic injury. Furthermore, in COX-2 knockout (COX-2(-/-)) mice, RGCs are resistant to ischemia-reperfusion injury. Finally, we performed time-lapse monitoring of RGC death after ischemia in Thy-1-EGFP; COX-2(-/-) mice. Our data show that COX-2 plays a crucial role in ischemia-reperfusion injury-induced RGC death. Inhibition of COX-2 activity may therefore be an effective therapy for neurodegenerative diseases of the retina and optic nerve.

Ligands for the epidermal growth factor receptor ErbB1, such as epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha), negatively regulate synaptic maturation of GABAergic neurons in the developing neocortex. Here, we evaluated the effects of these ligands in vivo on developing inhibitory neurons in the dentate gyrus. Hippocampal slices were prepared from postnatal mice repeatedly challenged with EGF or from transgenic mice overexpressing TGFalpha. We monitored paired pulse depression of field population spikes evoked by perforant path stimulation to estimate the strength of local inhibition. Administration of EGF increased the paired pulse ratio, suggesting a reduction of inhibitory strength. A similar reduction was observed in TGFalpha transgenic mice. Monitoring miniature and evoked synaptic currents, we estimated EGF effects on synaptic input and output of GABAergic neurons. EGF treatment diminished the amplitude of excitatory postsynaptic currents (EPSCs) in the GABAergic neurons without affecting their miniature EPSCs. EGF also affected output strength of the GABAergic neurons: The frequency of miniature inhibitory postsynaptic currents (IPSCs) and the evoked IPSC/evoked EPSC ratio were decreased in granule cells. In parallel, EGF down-regulated the protein level of vesicular GABA transporter. Thus, ErbB1 ligands influence GABAergic inhibitory synaptic transmission in the developing dentate gyrus.

Epidemiologic studies demonstrate significant environmental impact of maternal viral infection and obstetric complications on the risk of schizophrenia and indicate their detrimental influences on brain development in this disorder. Based on these findings, animal models for schizophrenia have been established using double stranded RNA, bacterial lipopolysaccharides, hippocampal lesion, or prenatal/perinatal ischemia. Key molecules regulating such immune/inflammatory reactions are cytokines, which are also involved in brain development, regulating dopaminergic and GABAergic differentiation, and synaptic maturation. Specific members of the cytokine family, such as interleukin-1, epidermal growth factor, and neuregulin-1, are induced after infection and brain injury; therefore, certain cytokines are postulated to have a central role in the neurodevelopmental defects of schizophrenia. Recently, to test this hypothesis, a variety of cytokines were administered to rodent pups. Cytokines administered in the periphery penetrated the immature blood-brain barrier and perturbed phenotypic neural development. Among the many cytokines examined, epidermal growth factor (or potentially other ErbB1 ligands) and interleukin-1 specifically induced the most severe and persistent behavioral and cognitive abnormalities, most of which were ameliorated by antipsychotics. These animal experiments illustrate that, during early development, these cytokine activities in the periphery perturbs normal brain development and impairs later psychobehavioral and/or cognitive traits. The neurodevelopmental and behavioral consequences of prenatal/perinatal cytokine activity are compared with those of other schizophrenia models and cytokine interactions with genes are also discussed in this review.

Addictive drugs and psychologic stress influence the input strength of ventral tegmental area (VTA) neurons, which implies the involvement of synaptic plasticity in dopaminergic neurons. Properties of excitatory synaptic transmission to the dopaminergic neurons have been analyzed using intracellular and patch-clamp recording methods. In the present study, we attempted to establish the field recording procedure in VTA slice preparations to monitor excitatory synaptic transmission. We evaluated this procedure using slice preparations from 6-hydroxydopamine (6-OHDA)-treated animals. In horizontal slices containing the VTA, electrical stimulation of anterior afferent fibers produced two distinct negative field potentials, presumably a fiber volley component and a transsynaptic component. Pharmacological analysis revealed that the transsynaptic component was composed of bicuculline-sensitive and CNQX-sensitive components. Neonatal 6-OHDA administration reduced approximately 90% of tyrosine hydroxylase expression in the VTA and eliminated more than 50% of the transsynaptic components. This result suggests that at least 50% of the observed transsynaptic component reflected the postsynaptic responses of the dopaminergic neurons.

Maternal stress, viral infection, and obstetric complications, which trigger cytokine signaling, are hypothesized to be involved in schizophrenia and its related disorders. The etiologic contribution of individual cytokines to such psychiatric disorders, however, remains to be evaluated. To estimate the impact of peripheral cytokine challenge on neurobehavioral development, we examined effects of four proinflammatory cytokines on rat neonates and their later behavioral performance. Sublethal doses of interleukin-1 alpha, interleukin-2, interleukin-6, or interferon-gamma were subcutaneously administered to rat pups for 9 days. These animals displayed alterations in physical development, including lower weight gain and/or accelerated eyelid opening. In addition, behavioral abnormalities related to fear/anxiety levels and sensorimotor gating emerged at different developmental stages, depending on the cytokine species administered. During juvenile stages, neonatal interleukin-2 treatment increased exploratory locomotor activity, whereas other cytokine treatments did not. At the post-puberty stage, however, the interleukin-2-induced abnormal motor activity became undetectable, whereas interleukin-1 alpha-treated rats developed abnormalities in startle response, prepulse inhibition (PPI), and social interaction. Subchronic treatment of an anti-psychotic drug, clozapine, ameliorated the impairment of prepulse inhibition without altering startle responses. These animal experiments illustrate that, during early postnatal development, inflammatory cytokine challenge in the periphery can induce future psycho-behavioral and/or cognitive impairments with various latencies, although the pathologic mechanisms underlying these abnormalities remain to be determined.

Cytokines have been implicated in the etiology or pathology of various psychiatric diseases of developmental origin such as autism and schizophrenia. Leukemia inhibitory factor (LIF) is induced by a variety of brain insults and known to have many influences on mature and immature nervous system. Here, we assessed the neurobehavioral and pathological consequences of peripheral administration of LIF in newborn rats. Subcutaneous LIF injection induced STAT3 phosphorylation in many brain regions and increased glial fibrillary acidic protein (GFAP) immunoreactivity in the neocortex, suggesting that LIF had direct effects in the central nervous system. The LIF-treated rats displayed decreased motor activity during juvenile stages, and developed abnormal prepulse inhibition in the acoustic startle test during and after adolescence. They displayed normal learning ability in active avoidance test, however. Brain neuronal structures and startle responses were grossly normal, except for the cortical astrogliosis during neonatal LIF administration. These results indicate that LIF induction in the periphery of the infant has a significant, but discrete impact on neurobehavioral development.

Novel protein synthesis is an essential element of various learning paradigms. Although pharmacological and genetic strategies have indicated the importance of translational activation in learning, the specific signaling pathways that are activated in the brain remain unclear. Here, we show that mammalian target of rapamycin (mTOR), a key serine/threonine protein kinase in translational control, is activated in hippocampus of the learning rat as revealed by in vitro kinase assay, Western blotting and immunohistochemistry. The substrates of mTOR, eukaryotic initiation factor 4E-binding protein (4EBP) and p70S6 kinase (p70S6K) are phosphorylated, and total protein synthesis is enhanced, in the learning hippocampus. Furthermore, the inhibition of mTOR by chronic infusion of rapamycin, a specific inhibitor of mTOR, into the ventricle retards the establishment of spatial learning. Thus, mTOR signaling is activated during learning, enhances translation, and plays a crucial role in the spatial learning.

Interleukin-1 (IL-1) mediates psychological stress responses by regulating monoamine metabolism and secretion of corticotropin-releasing factor, and is therefore, implicated in various psychiatric diseases. To evaluate the contribution of IL-1 signaling to the brain pathology of schizophrenia, we measured protein and/or mRNA levels for IL-1β and endogenous IL-1 receptor antagonist (IL-1RA) in the postmortem brain tissues of prefrontal and parietal cortex, putamen, and hypothalamus. Both protein and mRNA levels of IL-1RA were specifically decreased in the prefrontal cortex of schizophrenic patients, whereas IL-1β levels were not significantly altered in all the regions examined. The IL-1RA decrease was not correlated with the dose of antipsychotics given to patients. There was no influence of this illness on protein levels for IL-1 receptor type 1 in the prefrontal cortex, either. In contrast, IL-1RA serum levels were increased in schizophrenic patients, especially in drug-free patients, as reported previously. These findings suggest that chronic schizophrenia down-regulates IL-1RA production the prefrontal cortex, irrespective of its impact on the periphery. IL-1RA reduction might reflect an immunopathologic trait of the prefrontal region in schizophrenic patients.