1Rinsho Shinkeigaku 2001 Aug 41: 507-11
Title[A case of cerebellar degeneration with schizophrenia-like psychosis, severe iron deficiency, hypoceruloplasminemia and abnormal electroretinography: a new syndrome?].
AbstractA 33-year-old male patient began to develop schizophrenia-like symptoms and slowly progressive cerebellar ataxia. He was 170 cm tall and he had mild frontal baldness. Psychiatrically he was aconative, only willing to do nothing all day long after admission. He had neither hallucinations nor delusions, and his mental acuity was normal. Neurological examination revealed positive cerebellar signs including clumsiness in F-N-T and K-H-T and dysdiadochokinesis. He could neither stand up nor walk because of ataxia. The brain MRI showed severe cerebellar atrophy with normal basal ganglia. His EEG and the value of NCV were within normal range, whereas electroretinography showed a notable abnormality, pointing to the extremely small b-wave, resulting in a negative shape of the ERG. Although he was eating sufficiently, the level of serum iron and ferritin remained constantly low. The serum copper level was within normal range, whereas the serum ceruloplasmin level was mildly decreased. A hepatic biopsy indicated no accumulation of copper or iron. This case suggests the importance of the investigation of the serum iron and ceruloplasmin levels in patients who have cerebellar degeneration with psychosis.
SCZ Keywordsschizophrenia, schizophrenic
2Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Jan 32: 297-300
TitleRetinal dysfunctions in schizophrenia.
AbstractThe purpose of this study was to investigate the earliest stages of visual information processing using electroretinography (ERG) in patients with schizophrenia and bipolar disorder and to compare these values with those of healthy control volunteers. In the acute stage of the illness, patients with schizophrenia exhibited decreased a-wave amplitude (a measure of photoreceptor function) as compared with healthy controls. In patients with bipolar disorder, ERG measures were intact. At the baseline assessment, there was a significant negative relationship between a-wave amplitude and positive symptoms. After an 8-week follow-up period, clinical symptoms showed significant improvement and the amplitude of the a-wave significantly increased in patients with schizophrenia. At the follow-up assessment, there was no significant difference between patients with schizophrenia and controls. These results indicate that retinal dysfunctions are specific for schizophrenia, as compared with bipolar disorder, and are confined to the acute stage of the illness.
SCZ Keywordsschizophrenia, schizophrenic
3Biol. Psychiatry 2010 Feb 67: 270-4
TitleRetinal response to light in young nonaffected offspring at high genetic risk of neuropsychiatric brain disorders.
AbstractIn neuropsychiatric brain disorders, such as schizophrenia (SZ) and bipolar disorder (BD), the biased effect of chronic drug therapy and the toxic effect of illness once installed constitute obstacles to the identification of valid biomarkers. Such biomarkers could lie at the level of retinal function where anomalies have already been reported in adults suffering from neuropsychiatric disorders. Here, we report a specific electroretinographic (ERG) anomaly in young nonaffected and nonmedicated offspring at high genetic risk (HR) of these disorders.
Electroretinography was performed in 29 HR offspring having one parent affected by DSM-IV SZ or BD (mean age: 20.8 years, SD 4.4) and 29 healthy control subjects (mean age: 20.6 years, SD 4.2). The HRs' parents descended from multigenerational families affected by SZ or BD.
Rod ERG (b-wave amplitude at V(max)) in HRs was significantly lower than control subjects (p < .0001; effect size of -1.47), whereas the cone ERG V(max) showed no difference (p = .27). No effects of gender, age, and seasons of testing were observed. The anomaly in retinal response (rod V(max) b-wave amplitude) was observed independently of parents' diagnosis (SZ; p = .007, effect size of -1.09; BD: p < .0001, effect size of -1.88) and was present in both the younger and older HRs (effect size of -1.6 and -1.8, respectively).
A rod retinal response anomaly before the age of the disease incidence may represent an early and specific biomarker of risk with meaning for further genetic and prevention research.
SCZ Keywordsschizophrenia, schizophrenic
4Eur. J. Neurosci. 2012 Dec 36: 3628-35
TitleDifferential effects of blockade of ERG channels on gamma oscillations and excitability in rat hippocampal slices.
AbstractAgents such as sertindole and astemizole affect heart action by inducing long-QT syndrome, suggesting that apart from their neuronal actions through histamine receptors, 5-HT2 serotonin receptors and D2 dopamine receptors they also affect ether-a-go-go channels and particularly ether-a-go-go-related (ERG) potassium (K(+)) channels, comprising the K(v) 11.1, K(v) 11.2 and K(v) 11.3 voltage-gated potassium currents. Changes in ERG K(+) channel expression and activity have been reported and may be linked to schizophrenia [Huffaker, S.J., Chen, J., Nicodemus, K.K., Sambataro, F., Yang, F., Mattay, V., Lipska, B.K., Hyde, T.M., Song, J., Rujescu, D., Giegling, I., Mayilyan, K., Proust, M.J., Soghoyan, A., Caforio, G., Callicott, J.H., Bertolino, A., Meyer-LindenbERG, A., Chang, J., Ji, Y., Egan, M.F., GoldbERG, T.E., Kleinman, J.E., Lu, B. & WeinbERGer DR. (2009). Nat. Med., 15, 509-518; Shepard, P.D., Canavier, C.C. & Levitan, E.S. (2007). Schizophr Bull., 33, 1263-1269]. We have previously shown that histamine H1 blockers augment gamma oscillations (?) which are thought to be involved in cognition and storage of information. These effects were particularly pronounced for ? induced by acetylcholine. Here we have compared neuronal effects of three agents which interfere with ERG K(+) channels. We found that astemizole and sertindole, but not the K(v) 11 channel blocker E4031, augmented ? induced by acetylcholine in hippocampal slices. Kainate-induced ? were only affected by astemizole. Evoked responses induced by stratum radiatum stimulation in area CA1 revealed that only E4031 augmented stimulus-induced synaptic potentials and neuronal excitability. Our findings suggest that K(v) 11 channels are involved in neuronal excitability without clear effects on ? and that the effect of astemizole is related to actions on H1 receptors.
SCZ Keywordsschizophrenia, schizophrenic
5Nature 2013 Sep 501: 444-8
TitleThe structural mechanism of KCNH-channel regulation by the eag domain.
AbstractThe KCNH voltage-dependent potassium channels (ether--go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is composed of a Per-Arnt-Sim (PAS) domain and a PAS-cap domain, whereas the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD), which is connected to the pore through a C-linker domain. Many disease-causing mutations localize to these specialized intracellular domains, which underlie the unique gating and regulation of KCNH channels. It has been suggested that the eag domain may regulate the channel by interacting with either the S4-S5 linker or the CNBHD. Here we present a 2? resolution crystal structure of the eag domain-CNBHD complex of the mouse EAG1 (also known as KCNH1) channel. It displays extensive interactions between the eag domain and the CNBHD, indicating that the regulatory mechanism of the eag domain primarily involves the CNBHD. Notably, the structure reveals that a number of LQT2 mutations at homologous positions in human ERG, in addition to cancer-associated mutations in EAG channels, localize to the eag domain-CNBHD interface. Furthermore, mutations at the interface produced marked effects on channel gating, demonstrating the important physiological role of the eag domain-CNBHD interaction. Our structure of the eag domain-CNBHD complex of mouse EAG1 provides unique insights into the physiological and pathophysiological mechanisms of KCNH channels.
SCZ Keywordsschizophrenia, schizophrenic
6Prog Mol Biol Transl Sci 2014 -1 123: 53-82
TitleImplications of cellular models of dopamine neurons for schizophrenia.
AbstractMidbrain dopamine neurons are pacemakers in vitro, but in vivo they fire less regularly and occasionally in bursts that can lead to a temporary cessation in firing produced by depolarization block. The therapeutic efficacy of antipsychotic drugs used to treat the positive symptoms of schizophrenia has been attributed to their ability to induce depolarization block within a subpopulation of dopamine neurons. We summarize the results of experiments characterizing the physiological mechanisms underlying the ability of these neurons to enter depolarization block in vitro, and our computational simulations of those experiments. We suggest that the inactivation of voltage-dependent Na(+) channels, and, in particular, the slower component of this inactivation, is critical in controlling entry into depolarization block. In addition, an ether-a-go-related gene (ERG) K(+) current also appears to be involved by delaying entry into and speeding recovery from depolarization block. Since many antipsychotic drugs share the ability to block this current, ERG channels may contribute to the therapeutic effects of these drugs.
SCZ Keywordsschizophrenia, schizophrenic
7Cutan Ocul Toxicol 2014 Sep 33: 206-11
TitleGlyT1 inhibitor reduces oscillatory potentials of the electroretinogram in rats.
AbstractSelective inhibitors of glycine transporter type 1 (GlyT1) increase synaptic glycine concentrations and are being developed to treat cognitive and negative symptoms of schizophrenia. However, increases in systemic glycine levels have been associated with visual disturbances and electroretinogram (ERG) alternations.
To determine whether the selective GlyT1 inhibitor PF-03463275 causes changes in ERG responses in albino rats.
Male Sprague-Dawley rats were administered PF-03463275 subcutaneously at 1, 3 and 10?mg/kg 1?h prior to ERG acquisition. Scotopic and photopic luminance responses, photopic adaptometry and flicker responses were measured. Plasma and vitreous samples were obtained at necropsy for determination of PF-03463275 concentrations.
A dose-dependent reduction (up to ?70%) in the amplitude of the scotopic ERG oscillatory potentials (OPs) was observed following PF-03463275 administration. The amplitude of the OPs was also negatively correlated to the concentration of PF-03463275 in the vitreous humor (r?=?-0.64, p?ERG a-wave amplitude and latency no effects were observed on other ERG parameters tested.
We conclude that inhibition of the GlyT1 transporter in the retina causes ERG changes which may underlie recent reports of visual disturbance with GlyT1 inhibitors in clinical trials.
SCZ Keywordsschizophrenia, schizophrenic
8Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 129-34
TitleThe brain through the retina: the flash electroretinogram as a tool to investigate psychiatric disorders.
AbstractInvestigating the living brain remains one of the major obstacles in psychiatry research in order to better understand the biological underpinning of brain disorders. Novel approaches are needed to study brain functions indirectly. Since it is part of the central nervous system, retinal functions as measured with the flash electroretinogram (ERG) may reflect the central dysfunctions reported in psychiatric disorders. This review describes the flash ERG anomalies reported in patients with psychiatric disorders such as seasonal affective disorder, schizophrenia, autism spectrum disorder and drug addiction and discusses how changes in retinal functions might be used as biomarkers for psychiatric disorder as well as a potential aid to diagnosis in psychiatry.
SCZ Keywordsschizophrenia, schizophrenic
9Biol. Psychiatry 2014 Jul 76: 93-100
TitleGlycogen synthase kinase-3 overexpression replicates electroretinogram anomalies of offspring at high genetic risk for schizophrenia and bipolar disorder.
AbstractElectroretinogram (ERG) anomalies occur in patients with psychiatric disorders and represent potential biomarkers for diagnosis. For instance, decreased rod ERG (b-wave amplitude at Vmax) is a biological endophenotype in young offspring at high genetic risk (HR) for schizophrenia (SZ) and bipolar disorder (BD). Also, a decrease in cone a-wave and rod a- and b- wave was observed in SZ patients. However, the biological underpinning of these anomalies remains unknown. Several genetic variants associated with enhanced risk for SZ and/or BD can activate glycogen synthase kinase-3 isozymes (GSK3? and ?). Here we examined the potential contribution of GSK3? and ? in the modulation of the ERG.
Cone and rod ERGs were recorded in mice having increased (prpGSK3? mice) or reduced (GSK3?(+/-) mice) GSK3? expression and in GSK3? knockout (KO) mice.
In prpGSK3? mice, we observed a decrease in rod b-wave amplitude at Vmax, whereas enhanced b-wave amplitude at Vmax was found in GSK3?(+/-) mice. An increase in cone a- and b-wave amplitude at Vmax and in rod b-wave amplitude at Vmax was observed in GSK3?-KO mice.
GSK3 expression modulates some ERG parameters. The phenotype observed in prpGSK3? mice is consistent with observations made in HRs. ERG anomalies observed in GSK3?(+/-) and GSK3?-KO mice confirm an association between the rod and cone b-wave amplitude and the expression of GSK3 isozymes. Changes in GSK3 expression or activity may explain some ERG anomalies in HRs and patients, thus supporting the biological validity of ERG measurements as a valuable biomarker for psychiatric research.
SCZ Keywordsschizophrenia, schizophrenic
10Schizophr Res Cogn 2015 Jun 2: 46-55
TitleSchizophrenia and the eye.
AbstractAlthough visual processing impairments are common in schizophrenia, it is not clear to what extent these originate in the eye vs. the brain. This review highlights potential contributions, from the retina and other structures of the eye, tovisual processing impairments in schizophrenia and high-risk states. A second goal is to evaluate the status of retinal abnormalities as biomarkers for schizophrenia. The review was motivated by known retinal changes in other disorders (e.g., Parkinson's disease, multiple sclerosis), and their relationships to perceptual and cognitive impairments, and disease progression therein. The evidence reviewed suggests two major conclusions. One is that there are multiple structural and functional disturbances of the eye in schizophrenia, all of which could be factors in the visual disturbances of patients. These include retinal venule widening, retinal nerve fiber layer thinning, dopaminERGic abnormalities, abnormal ouput of retinal cells as measured by electroretinography (ERG), maculopathies and retinopathies, cataracts, poor acuity, and strabismus. Some of these are likely to be illness-related, whereas others may be due to medication or comorbid conditions. The second conclusion is that certain retinal findings can serve as biomarkers of neural pathology, and disease progression, in schizophrenia. The strongest evidence for this to date involves findings of widened retinal venules, thinning of the retinal nerve fiber layer, and abnormal ERG amplitudes. These data suggest that a greater understanding of the contribution of retinal and other ocular pathology to the visual and cognitive disturbances of schizophrenia is warranted, and that retinal changes have untapped clinical utility.
SCZ Keywordsschizophrenia, schizophrenic