Protein tyrosine phosphatases PTPδ, PTPσ, and LAR: presynaptic hubs for synapse organization

The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL-1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL-1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL-18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti-inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation.

The family of the interleukin-1 receptors

The interleukin-1 receptor family.

Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high-resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. A blinded review by two independent clinical cytogenetic laboratory directors of all large (>500 kb) rare CNVs in cases and well-matched controls showed that those deemed to be clinically significant were highly enriched in schizophrenia (16.4-fold increase, P 10 kb in size (1.5-fold increase, P = 0.0109) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and, (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, P = 0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism.

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Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays

The diagnostic criteria for schizophrenia in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV1) are based on the premise that it is a discrete illness entity, in particular, distinct from the affective psychoses. This assumption has persisted for more than a century, even though patients with a diagnosis of schizophrenia show a wide diversity of symptoms and outcomes, and no biological or psychological feature has been found to be pathognomonic of the disorder. However, there has been sustained, and indeed growing, criticism of the concept. For example, writing about the diagnosis of schizophrenia more than a decade ago,2 one of Britain's most sophisticated nosological experts, Ian Brockington, enjoined “It is important to loosen the grip which the concept of ‘schizophrenia’ has on the minds of psychiatrists. Schizophrenia is an idea whose very essence is equivocal, a nosological category without natural boundaries, a barren hypothesis. Such a blurred concept is ‘not a valid object of scientific enquiry’.”3 Should Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition(DSM-V), persist with the neo-Kraepelinian concept of schizophrenia with all its defects, or should it deconstruct psychosis into its component dimensions? In this article, we will address the question by considering 2 main themes, firstly, the role of culture and ethnicity in the diagnosis of psychosis, and secondly, a life course approach to understanding psychosis. We will then discuss whether more progress would be achieved in DSM-V by abandoning the familiar categorical system and instead moving to a dimensional system which rates both developmental impairment and symptom factor scores. However, we will begin by briefly reviewing the recent history of the classification of the psychoses.

Biological, life course, and cross-cultural studies all point toward the value of dimensional and developmental ratings in the classification of psychosis

Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees.

This paper focuses on the role of adoption and family relations as moderators of genetic risk for psychotic disorders. Participants included 184 adolescents in the Republic of Palau identified to be at genetic risk for schizophrenia and other psychotic disorders. Palau is an island nation in Micronesia with a lifetime prevalence of 1.99% for schizophrenia and 2.67% for psychotic disorders more broadly defined [24]. In Palauan culture, kinship adoption is a common cultural practice; 47 of the 184 participants had been adopted at an early age. The current study was designed to test the hypothesis that adoption would function as a protective factor among Palauan youth at genetic risk for the development of psychotic symptoms. Participants were evaluated for psychotic and other psychiatric symptoms using KSADS-PL [16]. Concurrently, the Youth Self Report [1] was used to assess the perceived quality of family relationships. Results indicated that adopted adolescents were more likely to develop psychotic symptoms than non-adopted adolescents. However, perceived family relations moderated the association between adoption status and psychotic symptoms, such that adopted adolescents with poorer family relations reported disproportionately higher rates of psychotic symptoms. Family relations also moderated the association between level of genetic risk and psychotic symptoms, independently of adoption status. Consistent with previous research, adolescents at high genetic risk who reported more positive family relations also reported fewer psychotic symptoms [4, 29].

Adoption, family relations and psychotic symptoms among Palauan adolescents who are genetically at risk for developing schizophrenia

Aim: This study was designed to identify early symptoms associated with the occurrence of psychosis during adolescence.



Method: Participants were recruited in the Republic of Palau, an isolated island nation in Micronesia with a prevalence rate for schizophrenia of 1.99%. Diagnostic interviews were used to obtain reports of early and current symptoms from 112 genetically high-risk (GHR) and 208 genetically low-risk (GLR) adolescents (ages 16–23). Based on current psychotic symptoms, participants were sorted into three groups: non-clinical, at-risk/symptomatic risk and clinically symptomatic.



Results: Multivariate analysis of variance revealed several between-group differences on rates of early symptoms. Most notably, youth who were in the GHR-clinically symptomatic group reported significantly higher rates of early marijuana use than GLR-clinically symptomatic youth, who were significantly more likely to report early symptoms of depression and behaviour disorders. In addition, several gender based differences in the link between early symptoms and adolescent onset psychosis were noted.



Conclusions: Findings are generally consistent with previous research on early indicators, though several unexpected findings suggest that results from this study may not be fully generalizable beyond this relatively isolated and culturally distinct Micronesian nation.

Stevenson Kuartei

Papers

Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees.

Adoption, family relations and psychotic symptoms among Palauan adolescents who are genetically at risk for developing schizophrenia

Early signs and symptoms of psychosis among Palauan adolescents.