epidermal-growth-factor and Schizophrenia

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune-inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors.

Topics: Animals; COVID-19; Disease Models, Animal; Dopamine; Epidermal Growth Factor; ErbB Receptors; Female; Mice; Mice, Transgenic; Pregnancy; Rats; Schizophrenia

Neuregulin-1 and epidermal growth factor (EGF) are implicated in the pathogenesis of schizophrenia. To test the developmental hypothesis for schizophrenia, we administered these factors to rodent pups, juveniles, and adults and characterized neurobiological and behavioral consequences. These factors were also provided from their transgenes or infused into the adult brain. Here we summarize previous results from these experiments and discuss those from neuropathological aspects. In the neonatal stage but not the juvenile and adult stages, subcutaneously injected factors penetrated the blood-brain barrier and acted on brain neurons, which later resulted in persistent behavioral and dopaminergic impairments associated with schizophrenia. Neonatally EGF-treated animals exhibited persistent hyperdopaminergic abnormalities in the nigro-pallido-striatal system while neuregulin-1 treatment resulted in dopaminergic deficits in the corticolimbic dopamine system. Effects on GABAergic and glutamatergic systems were transient or limited. Even in the adult stage, intracerebral administration and transgenic expression of these factors produced similar but not identical behavioral impairments, although the effects of intracerebral administration were reversible. These findings suggest that dopaminergic development is highly vulnerable to circulating ErbB ligands in the pre- and perinatal stages. Once maldevelopment of the dopaminergic system is established during early development, dopamine-associating behavioral deficits become irreversible and manifest at postpubertal stages.

Topics: Animals; Behavior, Animal; Blood-Brain Barrier; Dopamine; Dopaminergic Neurons; Epidermal Growth Factor; Humans; Mice; Neuregulin-1; Neurons; Rats; Schizophrenia

Epidermal growth factor (EGF) and neuregulin-1 (NRG) belong to the ErbB ligand family and both exert neurotrophic actions on midbrain dopamine neurons. According to the immune inflammatory hypothesis for schizophrenia, we have established rodent models for this illness by exposing their neonates to these cytokines. At post-pubertal stage, these animals develop various neurobehavioral abnormalities such as prepulse inhibition (PPI) and social interaction deficits. In this review, we introduce neurochemical features of the EGF-treated rats and NRG-treated mice, which exhibit persistent increases in tyrosine hydroxylase levels and dopamine release in the globus pallidus and prelimbic cortex (medial prefrontal cortex), respectively. Local blockade of the hyperdopaminergic state in EGF-treated rats ameliorates their behavioral deficits. These findings suggest that development of the midbrain dopamine system is vulnerable to circulating cytokines at perinatal and/or prenatal stages and potentially influences schizophrenia risk or neuropathology. The dopamine hypothesis for schizophrenia is re-evaluated with the obtained results as well as with published literatures in this review.

Topics: Animals; Disease Models, Animal; Dopamine; Epidermal Growth Factor; ErbB Receptors; Globus Pallidus; Humans; Ligands; Mice; Nerve Endings; Neuregulin-1; Prefrontal Cortex; Rats; Schizophrenia; Social Behavior Disorders; Tyrosine 3-Monooxygenase

The pathogenesis of schizophrenia has yet to be fully characterized. Gene-environment interactions have been found to play a crucial role in the vulnerability to this disease. Among various environmental factors, inflammatory immune processes have been most clearly implicated in the etiology and pathology of schizophrenia. Cytokines, regulators of immune/inflammatory reactions and brain development, emerge as part of a common pathway of genetic and environmental components of schizophrenia. Maternal infection, obstetric complications, neonatal hypoxia and brain injury all recruit cytokines to mediate inflammatory processes. Abnormal expression levels of specific cytokines such as epidermal growth factor, interleukins (IL) and neuregulin-1 are found both in the brain and peripheral blood of patients with schizophrenia. Accordingly, cytokines have been proposed to transmit peripheral immune/inflammatory signals to immature brain tissue through the developing blood-brain barrier, perturbing structural and phenotypic development of the brain. This cytokine hypothesis of schizophrenia is also supported by modeling experiments in animals. Animals treated with specific cytokines of epidermal growth factor, IL-1, IL-6, and neuregulin-1 as embryos or neonates exhibit schizophrenia-like behavioral abnormalities after puberty, some of which are ameliorated by treatment with antipsychotics. In this review, we discuss the neurobiological mechanisms underlying schizophrenia and novel antipsychotic candidates based on the cytokine hypothesis.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Cytokines; Disease Models, Animal; Epidermal Growth Factor; Humans; Models, Biological; Neuregulin-1; Schizophrenia

Abnormal development of the brain is implicated in the etiology and/or pathology of various psychiatric diseases, including schizophrenia. Current evidence indicates that neurotrophic factors can strongly influence neuronal phenotypic differentiation and subsequent neuronal function in synaptic plasticity. Among various neurotrophic factors, the expression of brain-derived neurotrophic factor(BDNF) and epidermal growth factor (EGF) is impaired in the brain as well as in the periphery of patients with schizophrenia. Based on this result, a novel animal model for schizophrenia has been established by perturbing the neurotrophic signaling during development. This review summarizes the latest progress of these studies.

Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Cell Differentiation; Cytokines; Disease Models, Animal; Epidermal Growth Factor; Humans; Nerve Growth Factors; Neuronal Plasticity; Neurons; Schizophrenia; Synapses

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.

Topics: Animals; Auditory Cortex; Disease Models, Animal; Early Growth Response Protein 1; Epidermal Growth Factor; Nerve Tissue Proteins; Proto-Oncogene Proteins c-fos; Rats; Schizophrenia

Rats elicit two types of ultrasonic vocalizations (USVs), positive (30-80 kHz; high pitch) and negative (10-30 kHz; low pitch) voices. As patients with schizophrenia often exhibit soliloquy-like symptoms, we explored whether an animal model for schizophrenia is similarly characterized by such self-triggered vocalizations. We prepared the animal model by administering an inflammatory cytokine, epidermal growth factor (EGF), to rat neonates, which later develop behavioral and electroencephalographic deficits relevant to schizophrenia. EGF model rats and controls at young (8-10 weeks old) and mature (12-14 weeks old) adult stages were subjected to acclimation, female pairing, and vocalization sessions. In acclimation sessions, low pitch USVs at the mature adult stage were more frequent in EGF model rats than in controls. In the vocalization session, the occurrences of low pitch self-triggered USVs were higher in EGF model rats in both age groups, although this group difference was eliminated by their risperidone treatment. Unlike conventional negative USVs of rats, however, the present low pitch self-triggered USVs had short durations of 10-30 ms. These results suggest the potential that self-triggered vocalization might serve as a translatable pathological trait of schizophrenia to animal models.

Topics: Animals; Disease Models, Animal; Epidermal Growth Factor; Female; Rats; Schizophrenia; Ultrasonics; Vocalization, Animal

Environmental risk factors that operate at foetal or neonatal levels increase the vulnerability to schizophrenia, plausibly via stress-immune activation that perturbs the epidermal growth factor (EGF) system, a system critical for neurodevelopment. We investigated potential associations between environmental insults and immune and EGF system changes through a maternal immune activation (MIA) model, using the precocial spiny mice (Acomys cahirinus). After mid-gestation MIA prepubescent offspring showed elevated NF-κB1 protein in nucleus accumbens, decreased EGFR in caudate putamen and a trend for increased PI3K-110δ in ventral hippocampus. Thus, prenatal stress may cause a heightened NF-κB1-mediated immune attenuation of EGF system signalling.

Topics: Animals; Behavior, Animal; Biomarkers; Brain; Disease Models, Animal; Epidermal Growth Factor; Female; Genes, erbB-1; Hippocampus; Mice; Motor Activity; Neurites; NF-kappa B; Pregnancy; Prenatal Exposure Delayed Effects; Schizophrenia; Signal Transduction

Previous studies have demonstrated that neurotrophic factors may play a critical role in the severity of clinical symptoms in schizophrenia. However, it remains unknown whether serum levels of epidermal growth factor (EGF) in schizophrenia are similar to those observed in the case of other neurotrophic factors. Therefore, we compared serum EGF concentrations in first-episode drug-naive (FEP) patients and medicated chronic schizophrenic patients with healthy controls in order to explore whether EGF levels are related to psychopathological symptoms. We measured the serum levels of EGF in 78 first-episode medication-naive schizophrenia patients, 76 medicated chronic schizophrenic patients, and 75 healthy controls using the sandwich ELISA method. Disease severity were measured using the positive and negative syndrome scale (PANSS). Serum EGF levels showed a significant decrease in schizophrenia patients in comparison to healthy subjects. Serum EGF levels in FEP patients are indistinguishable from chronic cases. EGF levels were related to PANSS general symptom subscales in both FEP never-medicated and medicated patients. It is interesting that serum EGF levels were negatively correlated with the PANSS cognitive subscales, with the exception of the patients with chronic schizophrenia. Our preliminary results indicated that EGF may play a role in this illness and that it could be used as a potential biomarker of disease severity. Moreover, EGF may be associated with cognitive subscales of PANSS in FEP patients. Future studies should investigate the relationship between EGF and cognitive function as measured using standardized neuropsychological assessments to identify potential biomarkers related with cognition.

Topics: Adolescent; Adult; Chronic Disease; Epidermal Growth Factor; Female; Humans; Male; Psychopathology; Schizophrenia; Schizophrenic Psychology; Young Adult

Schizophrenia in humans typically develops during and after adolescence; however, the biological underpinning for the specificity of this onset time window remains to be determined. In the present study, we investigated this knowledge gap using our own animal model for schizophrenia. Rodents and monkeys challenged with a cytokine, epidermal growth factor (EGF), as neonates are known to exhibit various behavioral and cognitive abnormalities at the post-pubertal stage. We used the EGF-challenged mice as an animal model for schizophrenia to evaluate the electrophysiological impact of this modeling on nigral dopamine neurons before and after puberty. In vivo single unit recording revealed that the burst firing of putative dopamine neurons in substantia nigra pars compacta was significantly higher in the post-pubertal stage of the EGF model than in that of control mice; in contrast, this difference was not observed in the pre-pubertal stage. The increase in burst firing was accompanied by a decline in Ca

Topics: Action Potentials; Animals; Cytokines; Dopaminergic Neurons; Epidermal Growth Factor; Mice; Schizophrenia; Substantia Nigra

Perinatal exposure to epidermal growth factor (EGF) induces various cognitive and behavioral abnormalities after maturation in non-human animals, and is used for animal models of schizophrenia. Patients with schizophrenia often display a reduction of mismatch negativity (MMN), which is a stimulus-change specific event-related brain potential. Do the EGF model animals also exhibit the MMN reduction as schizophrenic patients do? This study addressed this question to verify the pathophysiological validity of this model. Neonatal rats received repeated administration of EGF or saline and were grown until adulthood. Employing the odd-ball paradigm of distinct tone pitches, tone-evoked electroencephalogram (EEG) components were recorded from electrodes on the auditory and frontal cortices of awake rats, referencing an electrode on the frontal sinus. The amplitude of the MMN-like potential was significantly reduced in EGF-treated rats compared with saline-injected control rats. The wavelet analysis of the EEG during a near period of tone stimulation revealed that synchronization of EEG activity, especially with beta and gamma bands, was reduced in EGF-treated rats. Results suggest that animals exposed to EGF during a perinatal period serve as a promising neurodevelopmental model of schizophrenia.

Topics: Animals; Auditory Cortex; Beta Rhythm; Epidermal Growth Factor; Evoked Potentials; Frontal Lobe; Gamma Rhythm; Male; Rats; Rats, Sprague-Dawley; Schizophrenia

There is a growing interest in low-grade inflammatory and metabolic alterations in patients with chronic schizophrenia (SCH).. Inflammatory (tumor-necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukins [IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10], monocyte chemo-attractant protein-1 [MCP-1]) and growth factors (vascular endothelial growth factor [VEGF], epidermal growth factor [EGF]) were measured in blood serum samples of 105 SCH patients and 148 control subjects (CS). Simultaneously the clinical biomarkers (C-reactive protein [CRP], triglycerides [TG], low-density lipoprotein [LDL-c] and high-density lipoprotein [HDL-c] cholesterol, glycated hemoglobin [HbA1c]) were measured, and body mass index (BMI) was calculated for patients.. Several cyto-/chemokines (IFN-γ, MCP-1, IL-2, IL-6, IL-8 and IL-10) were significantly (P<0.0000001) elevated in SCH patients compared to CS. Odds ratios, obtained from logistic regression analyses, were significantly elevated for IL-2, IL-6, IL-10, INF-γ, and decreased for TNF-α in SCH group. Among the patients, higher IL-2, IL-6, INF-γ and lower MCP-1 levels as well as male gender were together significant (P<0.000001) predictors of higher HbA1c levels, and TG/HDL-c parameter was associated with ratios of INF-γ/IL-10 (P=0.004), and INF-γ/IL-4 (P=0.049), HbA1c (P=0.005), INF-γ (P=0.009), as well as LDL-c (P=0.02) levels.. IL-2, IL-6, IL-10 and IFN-γ were the most significant SCH-related markers among the measured cytokines in our patient group. Furthermore, significant associations between pro-/anti-inflammatory imbalance and HbA1c as well as cardio-metabolic risk marker (TG/HDL-c) were observed, indicating higher risks of diabetes and cardiovascular diseases among SCH patients.

Topics: Adult; Cytokines; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Humans; Inflammation; Male; Middle Aged; Obesity; Schizophrenia; Vascular Endothelial Growth Factor A

The current diagnostic tests for mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), have limitations. Inflammatory markers, growth factors, and oxidative stress markers are involved in the pathophysiology of mood disorders. A multi-assay biological diagnostic test combining these biomarkers might improve diagnostic efficiency. The plasma levels of soluble tumor necrosis factor receptor 2 (sTNFR2), epidermal growth factor (EGF), and myeloperoxidase were measured in 40 MDD patients, 40 BD patients and 40 controls in a Japanese population. We also investigated the plasma levels of these markers in 40 patients with schizophrenia to determine the utility of these markers in differential diagnosis. The plasma levels of sTNFR2 were significantly higher in BD and schizophrenia patients than in controls. The plasma levels of EGF and myeloperoxidase were significantly higher in patients with BD than in controls. The correct classification rate obtained from discriminant analysis with sTNFR2 and EGF between controls and mood disorders was 69.2%, with a sensitivity and specificity of 62.5% and 82.5%, respectively. The correct classification rate obtained from discriminant analysis with sTNFR2 and EGF between controls and BD was 85.0%, with a sensitivity and specificity of 77.6% and 92.5%, respectively. Our results suggest that sTNFR2 and EGF could be biological markers of BD. Further studies are needed to determine the utility of these markers in diagnostic tests for mood disorders.

Topics: Aged; Biomarkers; Bipolar Disorder; Case-Control Studies; Depressive Disorder, Major; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Mood Disorders; Peroxidase; Receptors, Tumor Necrosis Factor, Type II; Schizophrenia

Schizophrenia is a severe mental disorder that is likely to be strongly determined by genetic factors. To identify markers of disks, large homolog 2 (DLG2), FAT atypical cadherin 3 (FAT3), kinectin1 (KTN1), deleted in colorectal carcinoma (DCC), and glycogen synthase kinase-3β (GSK3β) that contribute to the genetic susceptibility to schizophrenia, we systematically screened for polymorphisms in the functional regions of these genes. A total of 22 functional single-nucleotide polymorphisms (SNPs) in 940 Chinese subjects were genotyped using SNaPshot. The results first suggested that the allelic and genotypic frequencies of the DCC polymorphism rs2229080 were nominally associated with schizophrenia. The patients were significantly less likely to be CC homozygous (P = 0.005, odds ratio [OR] = 0.635, 95 % confidence interval [95 % CI] = 0.462-0.873), and the schizophrenia subjects exhibited lower frequency of the C allele (P = 0.024, OR = 0.811, 95 % CI = 0.676-0.972). Regarding GSK3β, there was a significant difference in genotype distribution of rs3755557 between schizophrenia and healthy control subjects (P = 0.009). The patients exhibited a significantly lower frequency of the T allele of rs3755557 (P = 0.002, OR = 0.654, 95 % CI = 0.498-0.860). Our results point to the polymorphisms of DCC and GSK3β as contributors to the genetic basis of individual differences in the susceptibility to schizophrenia.

Topics: Adult; Cadherins; Case-Control Studies; DCC Receptor; Epidermal Growth Factor; Female; Gene Frequency; Genotype; Glycogen Synthase Kinase 3 beta; Guanylate Kinases; Humans; Male; Membrane Proteins; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Schizophrenia; Tumor Suppressor Proteins

Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.

Topics: 22q11 Deletion Syndrome; Adult; Animals; Animals, Newborn; Cells, Cultured; Disease Models, Animal; DNA Copy Number Variations; DNA Transposable Elements; Endogenous Retroviruses; Endonucleases; Epidermal Growth Factor; Female; Fibroblasts; Gene Ontology; Genetic Predisposition to Disease; Genome; Humans; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neurons; Phosphopyruvate Hydratase; Pluripotent Stem Cells; Poly I-C; Postmortem Changes; Prefrontal Cortex; Pregnancy; Pregnancy Proteins; Rett Syndrome; Risk Factors; RNA-Directed DNA Polymerase; Schizophrenia; Transfection

Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia.

Topics: Action Potentials; Animals; Animals, Newborn; Antipsychotic Agents; Disease Models, Animal; Electroencephalography; Epidermal Growth Factor; Excitatory Postsynaptic Potentials; Female; GABAergic Neurons; gamma-Aminobutyric Acid; Globus Pallidus; Humans; Male; Organ Culture Techniques; Rats; Rats, Sprague-Dawley; Risperidone; Schizophrenia; Substantia Nigra

Ligands for ErbB receptors, including epidermal growth factor (EGF) and neuregulin-1, have a neurotrophic activity on midbrain dopaminergic neurons and are implicated in the pathophysiology of schizophrenia. Although ErbB kinase inhibitors ameliorate behavioral deficits of the schizophrenia model that was established by hippocampal lesioning of rat pups, the antipsychotic action of ErbB kinase inhibitors and its general applicability to other models are not fully characterized. Using a different animal model, here, we examined whether and how ErbB kinase inhibitors ameliorate the behavioral endophenotypes relevant to schizophrenia. The animal model for schizophrenia was prepared by exposing neonatal rats to the cytokine EGF. Intraventricular infusion of the ErbB1 inhibitors ZD1839 and PD153035 in these animals ameliorated the deficits in startle response and prepulse inhibition in a dose-dependent manner. The deficits of latent inhibition of fear learning were also alleviated by ZD1839 with its limited effects on body weight gain or locomotor activity. ZD1839 infusion also decreased the busting activity of nigral dopamine (DA) neurons and reduced pallidal DA metabolism, a result that mimics the anti-dopaminergic profile of risperidone and haloperidol in this brain region. ErbB inhibitors appear to have anti-dopaminergic actions to alleviate some of the behavioral deficits common to animal models for schizophrenia.

Topics: Animals; Antipsychotic Agents; Brain Chemistry; Disease Models, Animal; Dopaminergic Neurons; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; Female; Gefitinib; Male; Motor Activity; Quinazolines; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia; Schizophrenic Psychology

Immune inflammatory processes in prenatal and perinatal stages are suggested to play crucial roles in the vulnerability to schizophrenia. Based upon this immune inflammatory hypothesis for schizophrenia, we have established animal models for this illness by subcutaneously administering cytokines or proinflammatory agents to rodent neonates. These models exhibit various schizophrenia-like behavioral abnormalities after puberty, most of which are sensitive to various antipsychotics. The experimental procedures are all simple and easily utilized by researchers unfamiliar with these models. The behavioral changes are reproducible and remarkable but do not accompany learning deficits. The molecular and cellular targets of these agents have also been investigated and partially characterized, such as the cortical GABAergic system, midbrain dopaminergic system and hippocampal glutamate system. In this chapter, we introduce the details of the procedure and discuss the potential application of these animal models to drug development for schizophrenia.

Topics: Animals; Behavior, Animal; Cytokines; Disease Models, Animal; Epidermal Growth Factor; Female; GABAergic Neurons; Inflammation; Inflammation Mediators; Mesencephalon; Mice; Neuregulin-1; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Schizophrenia

Epidermal growth factor (EGF) is one of the ErbB receptor ligands implicated in schizophrenia neuropathology as well as in dopaminergic development. Based on the immune inflammatory hypothesis for schizophrenia, neonatal rats are exposed to this cytokine and later develop neurobehavioral abnormality such as prepulse inhibition (PPI) deficit. Here we found that the EGF-treated rats exhibited persistent increases in tyrosine hydroxylase levels and dopamine content in the globus pallidus. Furthermore, pallidal dopamine release was elevated in EGF-treated rats, but normalized by subchronic treatment with risperidone concomitant with amelioration of their PPI deficits. To evaluate pathophysiologic roles of the dopamine abnormality, we administered reserpine bilaterally to the globus pallidus to reduce the local dopamine pool. Reserpine infusion ameliorated PPI deficits of EGF-treated rats without apparent aversive effects on locomotor activity in these rats. We also administered dopamine D1-like and D2-like receptor antagonists (SCH23390 and raclopride) and a D2-like receptor agonist (quinpirole) to the globus pallidus and measured PPI and bar-hang latencies. Raclopride (0.5 and 2.0 µg/site) significantly elevated PPI levels of EGF-treated rats, but SCH23390 (0.5 and 2.0 µg/site) had no effect. The higher dose of raclopride induced catalepsy-like changes in control animals but not in EGF-treated rats. Conversely, local quinpirole administration to EGF-untreated control rats induced PPI deficits and anti-cataleptic behaviors, confirming the pathophysiologic role of the pallidal hyperdopaminergic state. These findings suggest that the pallidal dopaminergic innervation is vulnerable to circulating EGF at perinatal and/or neonatal stages and has strong impact on the D2-like receptor-dependent behavioral deficits relevant to schizophrenia.

Topics: Aging; Animals; Animals, Newborn; Antipsychotic Agents; Behavior, Animal; Biomarkers; Catalepsy; Disease Models, Animal; Dopamine; Dopamine D2 Receptor Antagonists; Epidermal Growth Factor; Extracellular Space; Globus Pallidus; Humans; Immunohistochemistry; Interpersonal Relations; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reserpine; Risperidone; Schizophrenia; Tyrosine 3-Monooxygenase; Up-Regulation

Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N=74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N=87). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21-59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r=-0.387, P=0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia.

Topics: Adult; Brain-Derived Neurotrophic Factor; Chronic Disease; Epidermal Growth Factor; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Schizophrenia; Statistics, Nonparametric

Abnormality in cytokine signaling is implicated in the neuropathology of schizophrenia. Previously, we established an animal model for schizophrenia by administering epidermal growth factor (EGF) to neonatal rats. Here we investigated effects of the anthraquinone derivatives emodin (3-methyl-1,6,8-trihydroxyanthraquinone) and sennoside (bis-[D: -glucopyranosyl-oxy]-tetrahydro-4,4'-dihydroxy-dioxo[bianthracene]-2,2'-dicarboxylic acid) on behaviors of this model and EGF signaling. Subchronic oral administration of emodin (50 mg/kg) suppressed acoustic startle responses and abolished prepulse inhibition (PPI) deficits in this rodent model. ANCOVA revealed that emodin had distinct effects on PPI and startle responses. In contrast, sennoside (50 mg/kg) had no effects. Emodin attenuated weight gain initially during treatment but had no apparent effect on weight gain and locomotor activity thereafter. Application of emodin to neocortical cultures attenuated the phosphorylation of ErbB1 and ErbB2. We conclude that emodin can both attenuate EGF receptor signaling and ameliorate behavioral deficits. Therefore, emodin might be a novel class of a pro-drug for anti-psychotic medication.

Topics: Animals; Anthraquinones; Antipsychotic Agents; Behavior, Animal; Blotting, Western; Cathartics; Disease Models, Animal; Emodin; Epidermal Growth Factor; Neural Inhibition; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia; Senna Extract; Sennosides

Consistent with the hypothesis that neuroinflammatory processes contribute to the neuropathology of schizophrenia, the protein levels of epidermal growth factor (EGF) and its receptor ErbB1 are abnormal in patients with schizophrenia. To evaluate neuropathological significance of this abnormality, we established an animal model for behavioral deficits by administering EGF into the striatum and evaluated the effects of cyclooxygenase-2 (Cox-2) inhibitor celecoxib. Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models. Unilateral EGF infusion to the striatum lowered prepulse inhibition (PPI) in a dose-dependent manner and impaired latent learning of active shock avoidance without affecting basal learning ability. Bilateral EGF infusion similarly affected PPI. In contrast, EGF infusion to the nucleus accumbens did not induce a behavioral deficit. Intrastriatal EGF infusion also increased Cox-2 expression, elevated tyrosine hydroxylase activity, and upregulated the levels of dopamine and its metabolites. Subchronic administration of celecoxib (10 mg/kg, p.o.) ameliorated the abnormalities in PPI and latent learning as well as normalized dopamine metabolism. We conclude that this EGF-triggered neuroinflammatory process is mediated in part by Cox-2 activity and perturbs dopamine metabolism to generate neurobehavioral abnormalities.

Topics: Animals; Avoidance Learning; Corpus Striatum; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; Humans; Male; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia

Epidermal growth factor (EGF) is a well-known neurotrophic factor regulating the development of various neuronal cells, including dopaminergic neurons, and dysfunction of EGF signals has been demonstrated as a risk factor for schizophrenia. Recently, several researchers have investigated associations including age at onset (AAO) with EGF A61G functional polymorphism, but the results of these studies have been controversial. Thus, we investigated whether A61G plays a role in predisposition to schizophrenia and its effects on AAO. Our subjects included 190 patients with schizophrenia and 347 controls. We assessed three different points of AAO: age at first occurrence of positive psychotic symptoms, medication, and hospitalization as a patient with schizophrenia. We found no differences in allele and genotype frequencies between patients and controls or associations between A61G and AAOs across stratified points in the entire sample and in each gender. However, we found significant gender differences in patients with the AA genotype in all stratified points of AAOs. Subset analyses of G allele distribution between clinical subsets with an AAO cutoff of 20 years revealed that male patients with early onset schizophrenia were more likely to exhibit the common AA homozygote than male patients with adulthood onset schizophrenia. In conclusion, although we were unable to support an association between EGF A61G and schizophrenia, the AA genotype might play a disease-modifying role differentially according to gender.

Topics: Adolescent; Adult; Age of Onset; Alleles; Epidermal Growth Factor; Female; Humans; Male; Polymorphism, Genetic; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Sex Characteristics

The study population comprised 94 Finnish patients with DSM-IV diagnosis of schizophrenia. The patients were placed into two subgroups according to medication response to conventional neuroleptics. The aim of the study was to examine the frequency of tumor necrosis factor -308 (G > A) polymorphism in these patients and their 98 control subjects who were age- and gender-matched blood donors. Associations between TNFalpha -308 polymorphism alone and between the interaction of TNFalpha and epidermal growth factor gene polymorphisms, and medication response and age at onset of schizophrenia were also studied. The frequencies of TNFalpha A-allele were 11.7 % in patients and 12.8% in controls. The difference was not significant (p = 0.75). TNFalpha -308 polymorphism was not associated with medication response. However, patients with EGF AA and TNFalpha AG/AA genotype had a lower age at onset of schizophrenia compared with the rest of the patients not having this combination (20.0 years, 3.3 vs. 30.2 years, 10.1 mean + SD; p < 0.001). The results support earlier findings according to which TNFalpha polymorphism is not associated with the incidence of schizophrenia. On the other hand, the role of cytokines in schizophrenia may involve genetic interactions predisposing early onset of illness.

Topics: Adult; Age of Onset; Antipsychotic Agents; Epidermal Growth Factor; Female; Finland; Gene Frequency; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Psychiatric Status Rating Scales; Schizophrenia; Survival Analysis; Tumor Necrosis Factor-alpha

Low incidence of cancer in schizophrenia is one of the interesting puzzles in psychiatric field over decades. Analysis of genetic difference between schizophrenia and lung cancer might provide us with possible clues to understand molecular mechanisms of pathophysiology of schizophrenia. Epidermal growth factor (EGF), one of the potent growth promoting factors, has been studied for its roles in cancer development. EGF is also known to be involved in cognitive function. In order to analyze the genetic difference between schizophrenia and lung cancer, polymorphism of EGF gene was studied from 174 schizophrenia patients, 122 lung cancer patients and 132 controls in Korean population. Genotype frequency analysis of EGF gene (AluI restriction site, 5'-UTR, rs4444903) in the EGF gene was studied. The genotype and allele frequencies of the AluI polymorphism showed significant differences between schizophrenia and lung cancer patients [p<0.0001; p<0.0001, odds ratio (95% CI), 0.3690 (0.2600-0.5236)]. When compared with controls, schizophrenia patients showed no significant differences from controls in genotype and allele frequencies [p=0.5151; p=0.3516, odds ratio (95% CI), 0.8589 (0.6235-1.1830)]. However, lung cancer patients showed significant differences from controls in genotype and allele frequencies [p<0.0001; p<0.0001, odds ratio (95% CI), 2.3275 (1.6082-3.3687)]. These results indicate that schizophrenia is not associated with AluI polymorphism of EGF gene and EGF gene polymorphism is different between schizophrenia and lung cancer patients.

Topics: 5' Untranslated Regions; Adult; Case-Control Studies; Epidermal Growth Factor; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Korea; Lung Neoplasms; Male; Middle Aged; Odds Ratio; Polymorphism, Restriction Fragment Length; Schizophrenia

Epidermal growth factor (EGF) signal regulates the development of dopaminergic neurons and monoamine metabolism. It is suggested that EGF protein levels are decreased in the brain and blood of patients with schizophrenia. A recent study has reported that a polymorphism in EGF gene (rs4444903) is associated with schizophrenia in Finnish men. To confirm this association for another population in larger samples, we conducted a case-control association study on a Japanese population (337 cases and 421 controls). No significant difference was observed in both the allelic and genotype distribution between cases and controls in women, men and total samples. Our results suggest that the polymorphism in EGF gene might not confer increased susceptibility for schizophrenia in a Japanese population.

Topics: Adult; Alleles; Asian People; Epidermal Growth Factor; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Schizophrenia

A recent report demonstrated that serum levels of epidermal growth factor (EGF) were significantly decreased in patients with schizophrenia, suggesting that impaired EGF signaling might be associated with the pathophysiology of schizophrenia. Our goal in the present study was to determine whether serum levels of EGF are altered in patients with schizophrenia. We found that serum levels of EGF in drug-naive (n = 15) or medicated patients (n = 25) with schizophrenia did not differ from those of age- and sex-matched normal controls (n = 40). However, we found a significant correlation between serum EGF levels and BPRS scores in the combined groups of patients. Therefore, our results do not support the claim that EGF plays a role in the pathogenesis of schizophrenia, but they suggest that EGF may serve as a state marker, that is, as an index of symptom-linked deficits.

Topics: Adult; Brief Psychiatric Rating Scale; Diagnostic and Statistical Manual of Mental Disorders; Epidermal Growth Factor; Female; Humans; Male; Nerve Growth Factors; Schizophrenia

Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism.

Topics: Adult; Confidence Intervals; Epidermal Growth Factor; Female; Finland; Gene Frequency; Humans; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic; Retrospective Studies; Schizophrenia

Epidermal growth factor (EGF) and its structurally related proteins are implicated in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. There are EGF and EGF receptor abnormalities in both brain tissues and blood from schizophrenic patients. We administered EGF to neonatal rats to transiently perturb endogenous EGF receptor signaling and evaluated the neurobehavioral consequences. EGF-treatment-induced transient impairment in tyrosine hydroxylase expression. The animals grew normally, exhibited normal weight increase, glial growth, and gross brain structures, and later lost the tyrosine hydroxylase abnormality. During and after development, however, the rats began to display various behavioral abnormalities. Abnormal sensorimotor gating was apparent, as measured by deficits in prepulse inhibition of acoustic startle. Motor activity and social interaction scores of the EGF-treated animals were also impaired in adult rats, though not in earlier developmental stages. In parallel, there was a significant abnormality in dopamine metabolism in the brain stem of the adult animals. Gross learning ability appeared to be normal as measured by active avoidance. These behavioral alterations, which are often present in schizophrenic models, were ameliorated by subchronic treatment with clozapine. Although the molecular and/or physiologic background(s) of these behavioral abnormalities await further investigation, the results of the present experiment indicate that abnormal EGF receptor stimulation given during limited neonatal stages can result in severe and persistent cognitive/behavioral dysfunctions, which appear only in adulthood.

Topics: Animals; Animals, Newborn; Avoidance Learning; Behavior, Animal; Blood-Brain Barrier; Brain; Brain Chemistry; Cognition; Epidermal Growth Factor; ErbB Receptors; Female; Motor Activity; Motor Neurons; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia; Signal Transduction; Social Behavior

Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia.

Topics: Adult; Aged; Aged, 80 and over; Animals; Epidermal Growth Factor; ErbB Receptors; Female; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Prosencephalon; Rats; Rats, Wistar; Schizophrenia; Transforming Growth Factor alpha