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Different Paths to Core Pathology: The Equifinal Model of the Schizophrenia Syndrome.

ABSTRACT: Schizophrenia is a clinically heterogeneous disorder that is perhaps more accurately characterized as "the schizophrenia syndrome." This clinical heterogeneity is reflected in the heterogeneous neurobiological presentations associated with the illness. Moreover, even highly specific neural aberrations that are associated with distinct symptoms of schizophrenia are linked to a wide range of risk factors. As such, any individual with schizophrenia likely has a particular set of risk factors that interact and converge to cross the disease threshold, forming a particular etiology that ultimately generates a core pathophysiology. This core pathophysiology may then produce 1 or more symptoms of schizophrenia, leading to common symptoms across individuals in spite of disparate etiologies. As such, the schizophrenia syndrome can be considered as anequifinalentity: a state of dysfunction that can arise from different upstream etiologies. Moreover, schizophrenia etiologies are multifactorial and can involve the interactive effects of a broad range of genetic, environmental, and developmental risk factors. Through a consideration of how disparate etiologies, caused by different sets of risk factors, converge on the same net dysfunction, this paper aims to model the equifinal nature of schizophrenia symptoms. To demonstrate the equifinal model, we discuss how maternal infection and adolescent cannabis use, 2 recognized schizophrenia risk factors, may interact with other genetic, environmental, and/or developmental risk factors to cause the conserved clinical presentation of impaired working memory.

SUBMITTER: Green IW

PROVIDER: S-EPMC4838077 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Different Paths to Core Pathology: The Equifinal Model of the Schizophrenia Syndrome.

Green Isobel W IW Glausier Jill R JR

Schizophrenia bulletin 20150920 3

Schizophrenia is a clinically heterogeneous disorder that is perhaps more accurately characterized as "the schizophrenia syndrome." This clinical heterogeneity is reflected in the heterogeneous neurobiological presentations associated with the illness. Moreover, even highly specific neural aberrations that are associated with distinct symptoms of schizophrenia are linked to a wide range of risk factors. As such, any individual with schizophrenia likely has a particular set of risk factors that i ...[more]

PMID: 26392629

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Project description:Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.

Dataset Information

Different Paths to Core Pathology: The Equifinal Model of the Schizophrenia Syndrome.

Publications

Different Paths to Core Pathology: The Equifinal Model of the Schizophrenia Syndrome.

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