Timing of maternal immune activation and sex influence schizophrenia-relevant cognitive constructs and neuregulin and GABAergic pathways.

Maternal immune activation (MIA) during pregnancy is an established environmental risk factor for schizophrenia. Timing of immune activation exposure as well as sex of the exposed offspring are critical factors in defining the effects of MIA. However, the specificity of MIA on the component structure of schizophrenia, especially cognition, has been difficult to assess due to a lack of translational validity of maze-like testing paradigms. We aimed to assess cognitive domains relevant to schizophrenia using highly translational touchscreen-based tasks in male and female mice exposed to the viral mimetic, poly(I:C) (5 mg/k, i.p.), during early (gestational day (GD) 9-11) and late (GD13-15) gestational time points. Gene expression of schizophrenia candidate pathways were assessed in fetal brain immediately following poly(I:C) exposure and in adulthood to identify its influence on neurodevelopmental processes. Sex and window specific alterations in cognitive performance were found with the early window of MIA exposure causing female-specific disruptions to working memory and reduced perseverative behaviour, while late MIA exposure caused male-specific changes to working memory and deficits in reversal learning. GABAergic specification marker, Nkx2.1 gene expression was reduced in fetal brains and reelin expression was reduced in adult hippocampus of both early and late poly(I:C) exposed mice. Neuregulin and EGF signalling were initially upregulated in the fetal brain, but were reduced in the adult hippocampus, with male mice exposed in the late window showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and adult brain, but again, adult reductions were specific to male mice exposed at the late time point. Overall, we show that cognitive constructs relevant to schizophrenia are altered by in utero exposure to maternal immune activation, but are highly dependent on the timing of infection and the sex of the offspring. Glutamatergic and epidermal growth factor pathways were similarly altered by MIA in a timing and sex dependent manner, while MIA-induced GABAergic deficits were independent of timing or sex.

Bazedoxifene - a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory.

Over 20 years of accumulated evidence has shown that the major female sex hormone 17ß-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clinical use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1) cross the blood-brain barrier, 2) rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3) activate neural estrogen response element (ERE)-dependent gene transcription. Using liquid chromatography-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute intraperitoneal injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clinical applicability.

Neuregulin-1 (NRG1) polymorphisms linked with psychosis transition are associated with enlarged lateral ventricles and white matter disruption in schizophrenia.

BACKGROUND: Two single-nucleotide polymorphisms (SNPs) (rs4281084 and rs12155594) within the neuregulin-1 (NRG1) gene have been associated with psychosis transition. However, the neurobiological changes associated with these SNPs remain unclear. We aimed to determine what relationship these two SNPs have on lateral ventricular volume and white matter integrity, as abnormalities in these brain structures are some of the most consistent in schizophrenia. METHODS: Structural (n = 370) and diffusion (n = 465) magnetic resonance imaging data were obtained from affected and unaffected individuals predominantly of European descent. The SNPs rs4281084, rs12155594, and their combined allelic load were examined for their effects on lateral ventricular volume, fractional anisotropy (FA) as well as axial (AD) and radial (RD) diffusivity. Additional exploratory analyses assessed NRG1 effects on gray matter volume, cortical thickness, and surface area throughout the brain. RESULTS: Individuals with a schizophrenia age of onset ⩽25 and a combined allelic load ⩾3 NRG1 risk alleles had significantly larger right (up to 50%, p adj = 0.01) and left (up to 45%, p adj = 0.05) lateral ventricle volumes compared with those with allelic loads of less than three. Furthermore, carriers of three or more risk alleles, regardless of age of onset and case status, had significantly reduced FA and elevated RD but stable AD in the frontal cortex compared with those carrying fewer than three risk alleles. CONCLUSIONS: Our findings build on a growing body of research supporting the functional importance of genetic variation within the NRG1 gene and complement previous findings implicating the rs4281084 and rs12155594 SNPs as markers for psychosis transition.

Sensory integration deficits support a dimensional view of psychosis and are not limited to schizophrenia.

Visual dysfunction is commonplace in schizophrenia and occurs alongside cognitive, psychotic and affective symptoms of the disorder. Psychophysical evidence suggests that this dysfunction results from impairments in the integration of low-level neural signals into complex cortical representations, which may also be associated with symptom formation. Despite the symptoms of schizophrenia occurring in a range of disorders, the integration deficit has not been tested in broader patient populations. Moreover, it remains unclear whether such deficits generalize across other sensory modalities. The present study assessed patients with a range of psychotic and nonpsychotic disorders and healthy controls on visual contrast detection, visual motion integration, auditory tone detection and auditory tone integration. The sample comprised a total of 249 participants (schizophrenia spectrum disorder n=98; bipolar affective disorder n=35; major depression n=31; other psychiatric conditions n=31; and healthy controls n=54), of whom 178 completed one or more visual task and 71 completed auditory tasks. Compared with healthy controls and nonpsychotic patients, psychotic patients trans-diagnostically were impaired on both visual and auditory integration, but unimpaired in simple visual or auditory detection. Impairment in visual motion integration was correlated with the severity of positive symptoms, and could not be accounted for by a reduction in processing speed, inattention or medication effects. Our results demonstrate that impaired sensory integration is not specific to schizophrenia, as has previously been assumed. Instead, sensory deficits are closely related to the presence of positive symptoms independent of diagnosis. The finding that equivalent integrative sensory processing is impaired in audition is consistent with hypotheses that propose a generalized deficit of neural integration in psychotic disorders.

Meta-analysis reveals associations between genetic variation in the 5' and 3' regions of Neuregulin-1 and schizophrenia.

Genetic, post-mortem and neuroimaging studies repeatedly implicate neuregulin-1 (NRG1) as a critical component in the pathophysiology of schizophrenia. Although a number of risk haplotypes along with several genetic polymorphisms in the 5' and 3' regions of NRG1 have been linked with schizophrenia, results have been mixed. To reconcile these conflicting findings, we conducted a meta-analysis examining 22 polymorphisms and two haplotypes in NRG1 among 16 720 cases, 20 449 controls and 2157 family trios. We found significant associations for three polymorphisms (rs62510682, rs35753505 and 478B14-848) at the 5'-end and two (rs2954041 and rs10503929) near the 3'-end of NRG1. Population stratification effects were found for the rs35753505 and 478B14-848(4) polymorphisms. There was evidence of heterogeneity for all significant markers and the findings were robust to publication bias. No significant haplotype associations were found. Our results suggest genetic variation at the 5' and 3' ends of NRG1 are associated with schizophrenia and provide renewed justification for further investigation of NRG1's role in the pathophysiology of schizophrenia.

Decreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects.

BACKGROUND: Dysfunction of the cholinergic muscarinic receptors has been implicated in the pathology of bipolar disorder and major depressive disorder. However, there is conflicting evidence regarding the association between individual muscarinic receptors and the two disorders. METHODS: We used the muscarinic receptor selective radioligands [3H]pirenzepine, [3H]AFDX-384 and [3H]4-DAMP to measure the levels of muscarinic(1) (CHRM1) and muscarinic(4) (CHRM4) receptors, muscarinic(2) (CHRM2) and muscarinic(4) (CHRM4) receptors and muscarinic(3) (CHRM3) receptor, respectively. Radioligand binding was measured in Brodmann's area (BA) 10 of the rostral prefrontal cortex, BA 46 of the dorsolateral prefrontal cortex and BA 40 of the parietal cortex in the post-mortem CNS from subjects with bipolar disorder or major depressive disorder and control subjects. RESULTS: [3H]AFDX-384 binding was decreased in BA 46 in both bipolar disorder (p<0.01) and major depressive disorder (p<0.05). [3H]4-DAMP binding was decreased in BA 10 in bipolar disorder (p<0.05) but not major depressive disorder (p>0.05). [3H]AFDX-384 and [3H]4-DAMP binding were unaltered in any other cortical region examined for either disorder (p>0.05). [3H]pirenzepine binding was not significantly altered in either disorder in any cortical region examined (p>0.05). LIMITATIONS: 9 bipolar disorder, 9 major depressive disorder and 19 control subjects were used in the study. CONCLUSION: Our data is consistent with previously published data implicating a role for CHRM2 receptors in the pathology of bipolar and major depressive disorder. The demonstration of a novel association between decreased CHRM3 receptor expression and bipolar disorder suggests bipolar and major depressive disorder differs in the underlying nature of their cholinergic dysfunction.

Decreased cortical muscarinic receptors define a subgroup of subjects with schizophrenia.

Schizophrenia is widely acknowledged as being a syndrome, consisting of an undefined number of diseases probably with differing pathologies. Although studying a syndrome makes the identification of an underlying pathology more difficult; neuroimaging, neuropsychopharmacological and post-mortem brain studies all implicate muscarinic acetylcholine receptors (CHRM) in the pathology of the disorder. We have established that the CHRM1 is selectively decreased in the dorsolateral prefrontal cortex of subjects with schizophrenia. To expand this finding, we wanted to ascertain whether decreased cortical CHRMs might (1) define a subgroup of schizophrenia and/or (2) be related to CHRM1 genotype. We assessed cortical [(3)H]pirenzepine binding and sequenced the CHRM1 in 80 subjects with schizophrenia and 74 age sex-matched control subjects. Kernel density estimation showed that [(3)H]pirenzepine binding in BA9 divided the schizophrenia, but not control, cohort into two distinct populations. One of the schizophrenia cohorts, comprising 26% of all subjects with the disorder, had a 74% reduction in mean cortical [(3)H]pirenzepine binding compared to controls. We suggest that these individuals make up 'muscarinic receptor-deficit schizophrenia' (MRDS). The MRDS could not be separated from other subjects with schizophrenia by CHRM1 sequence, gender, age, suicide, duration of illness or any particular drug treatment. Being able to define a subgroup within schizophrenia using a central biological parameter is a pivotal step towards understanding the biochemistry underlying at least one form of the disorder and may represent a biomarker that can be used in neuroimaging.

Regional update: Cambodia.

Cambodia is a developing south-east Asian country located in the fertile Mekong delta. Its recent past has been complicated by European colonialism and internal conflict. Health including mental health services are limited and sparse in regional and rural areas. Very constrained public mental health facilities and services are hampered by a shortage of a skilled workforce and insufficient training programs. The recent formation of the Mental Health Association of Cambodia promises to be a positive step forward in promoting mental health throughout the country.

Acculturation is associated with the prevalence of tardive dyskinesia and akathisia in community-treated patients with schizophrenia.

OBJECTIVE: Ethnicity is a risk factor for tardive dyskinesia (TD) and other antipsychotic drug-induced movement disorders (ADIMD). It is unclear whether this association is mediated through genetic, environmental or cultural factors individually or in combination. This pilot study aimed to explore this interaction by determining if acculturation in migrant groups contributed to the prevalence of ADIMD. METHOD: Culturally diverse but relatively genetically homogeneous (white Caucasian) patients with schizophrenia (n = 40) treated at a single site were assessed for the presence of ADIMD and level of acculturation. RESULTS: Higher levels of acculturation correlated with an increased prevalence of TD and akathisia but not Parkinsonism. The level of acculturation significantly predicted TD. CONCLUSION: This study identifies for the first time that acculturation significantly contributes to the prevalence of TD and akathisia but not Parkinsonism in culturally diverse migrant populations and must be accounted for when explaining ethnic variation in rates of ADIMD.

Schizophrenia and bipolar affective disorder: perspectives for the development of therapeutics.

Schizophrenia and bipolar disorder remain two of the most severe and difficult to treat psychotic disorders hampered by our poor understanding of their pathologies. The development of typical antipsychotic drugs opened an avenue of investigation through the dopamine D2 receptor in schizophrenia. With the reintroduction of the atypical antipsychotic clozapine came the development of a new generation of atypical agents and hypotheses challenging the centrality of this receptor in explaining antipsychotic effects. Evaluation of these competing theories does not provide sufficient evidence to displace the importance of the dopamine D2 receptor in antipsychotic efficacy, but does raise limitations of it as an explanatory hypothesis. Further, the treatment of other symptom domains in schizophrenia remains relatively neglected and open for the development of novel therapies. Similar to schizophrenia, bipolar disorder presents a diversity of clinical states but unlike schizophrenia, its mainstay of treatment, lithium, has not had a clear receptor target impeding understanding of the disorder's pathology and treatment. This has pushed investigation into other domains emphasising a number of intracellular signalling pathways and glial-neuronal interactions. The heavy genetic loading of bipolar disorder has allowed linkage analyses to identify a number of putative regions, however, the diversity of phenotypes complicates such studies. Polymorphisms of candidate genes have yielded potential leads such as dopamine beta hydroxylase in mood disorder and the serotonin transporter for treatment response. It is anticipated that combiningthe above approaches may hold promise for the development of more effective treatments.

Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder.

OBJECTIVES: The purpose of this study was to determine whether there are changes in the density of ionotropic glutamate receptors in the hippocampus of subjects with bipolar disorder. METHODS: Using in situ radioligand binding with semiquantitative autoradiography, we measured the density of [3H]MK-801, [3H]CGP39653, [3H]AMPA and [3H]kainate binding in hippocampi, obtained postmortem, from eight subjects with type 1 bipolar disorder and 8 age- and sex-matched controls. RESULTS: In subjects with bipolar disorder there were significant decreases in the density of [3H]MK-801 binding in the Cornu Ammonis (CA) 3 (mean +/- SEM; 108.8 +/- 12.2 versus 166.2 +/- 18.0 fmol/mg ETE, p < 0.005) as well as the pyramidal (102.8 +/- 9.2 versus 136.6 +/- 11.2 fmol/mg ETE, p < 0.05) and polymorphic (21.73 +/- 6.5 versus 53.26 +/- 11.6 fmol/mg ETE, p < 0.05) layers of the subiculum. In addition, two-way analysis of variance (ANOVA) revealed a decrease in the density of [3H]CGP39653 binding across the hippocampal formation in bipolar subjects, which did not reach significance in any subregion. There were no changes in the densities of [3H]AMPA or [3H]kainate binding in these subjects. CONCLUSIONS: [3H]CGP39653 and [3H]MK-801 bind to the glutamate binding site and open ion channel of the n-methyl-d-aspartate (NMDA) receptor, respectively. Therefore, these data suggest that there is a decrease in the number of open ion channels associated with no significant change in the apparent density of NMDA receptors in regions of the hippocampus from subjects with bipolar disorder.

Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use.

A number of studies suggested that cannabis use can cause or exacerbate psychoses and may increase the risk of developing schizophrenia. These findings suggest that changes in the cannabinoid system of the brain may be involved in the pathology of schizophrenia. To determine whether changes in the cannabinoid system were present in the brains of subjects with schizophrenia, we used in situ radioligand binding and autoradiography to measure the binding of [3H]CP-55940 to the cannabinoid-1 receptor in the dorsolateral prefrontal cortex (Brodmann's area 9), caudate-putamen and areas of the temporal lobe from schizophrenic and control subjects, some of whom had ingested cannabis close to death. There was an increase in the density of [3H]CP-55940 binding to cannabinoid-1 receptors in the dorsolateral prefrontal cortex from subjects with schizophrenia (mean+/-S.E.M.: 142+/-9.9 vs 119+/-6.6fmol/mg estimated tissue equivalents; P<0.05) that was independent of recent cannabis ingestion. There was an increase in the density of cannabinoid-1 receptors in the caudate-putamen from subjects who had recently ingested cannabis (151+/-9.0 vs 123+/-7.2fmol/mg estimated tissue equivalents; P<0.05) that was independent of diagnoses. These data indicate that there are changes in cannabinoid-1 receptors in the dorsolateral prefrontal cortex that may prove to be associated with the pathology of schizophrenia. By contrast, changes in the density of cannabinoid-1 receptors may occur in the caudate-putamen in response to cannabis ingestion.

Typical and atypical neuroleptic drugs decrease platelet 3H-dopamine uptake in the rat.

Reports of opposing changes in platelet 3H-dopamine uptake in neuroleptic-free versus neuroleptic-treated schizophrenic subjects have suggested an effect of neuroleptic treatment on this measure. We examined platelet 3H-dopamine uptake in rats treated with haloperidol or clozapine to determine if such treatment did affect platelet 3H-dopamine uptake. Neuroleptic drug treatment reduced platelet 3H-dopamine uptake in a dose- and time-dependent manner. After up to 4 weeks of treatment, these effects were reversed by the discontinuation of neuroleptic drug treatment. These data suggest that the effect of neuroleptic treatment in studies of platelet 3H-dopamine uptake could account for the variable findings in schizophrenia.

Platelet [3H]dopamine uptake is differentially affected by neuroleptic drug treatment in schizophrenia and schizophreniform disorder.

1. The uptake of [3H] dopamine was measured using platelet-rich plasma (PRP) from neuroleptic-free subjects and again, in some cases, after the subject had been treated with neuroleptic drugs. 2. There were no differences in [3H]dopamine uptake by PRP in subjects who were or were not mentally ill. 3. After treatment with neuroleptic drugs the Km for platelet [3H] dopamine uptake had increased in 76% of subjects with schizophrenia and 87% of subjects with schizophreniform disorder. Similarly, the Vmax for platelet [3H]dopamine uptake had increased in 81% of the subjects with schizophrenia and 86% of the subjects with schizophreniform disorder. 4. By contrast, the Km for platelet [3H]dopamine uptake had decreased in 94% of subjects who had a psychoses associated with an illness other than schizophrenia or schizophreniform-disorder whilst the Vmax for platelet [3H]dopamine uptake also decreased by 94% in these subjects. 5. In subjects with psychoses, platelet [(3)H] dopamine uptake is differentially altered during neuroleptic drug treatment depending on diagnosis.

The development of a method to measure [3H] dopamine uptake by washed platelets provides no evidence for circulating inhibitors of platelet dopamine uptake in schizophrenia.

Altered [3H] dopamine uptake by platelet-rich plasma (PRP) has been reported in some subjects with schizophrenia (Rotman et al 1980; Dean et al 1990). As platelet dopamine uptake was measured using PRP, it was not possible to determine if the changes in schizophrenia were intrinsic to the platelet or due to plasma factors. Furthermore, the constraints of plasma as a medium for platelet suspension has hindered the study of the physiological requirements of platelet dopamine uptake. A method is now reported that allows platelets to be suspended in a controlled medium while preserving the dopamine uptake mechanism of the platelet. Dopamine uptake by platelets in a controlled medium was dependent on temperature, energy, sodium, and chloride. Furthermore, plasma from subjects with schizophrenia and schizophreniform disorder did not significantly alter [3H] dopamine uptake by platelets compared to the effect of plasma from control subjects. Hence, these data provide no evidence for a circulating inhibitor of platelet [3H] dopamine uptake in plasma from subjects with schizophrenia.