Molecular substrates of schizophrenia: homeostatic signaling to connectivity.

Schizophrenia (SZ) is a devastating psychiatric condition affecting numerous brain systems. Recent studies have identified genetic factors that confer an increased risk of SZ and participate in the disease etiopathogenesis. In parallel to such bottom-up approaches, other studies have extensively reported biological changes in patients by brain imaging, neurochemical and pharmacological approaches. This review highlights the molecular substrates identified through studies with SZ patients, namely those using top-down approaches, while also referring to the fruitful outcomes of recent genetic studies. We have subclassified the molecular substrates by system, focusing on elements of neurotransmission, targets in white matter-associated connectivity, immune/inflammatory and oxidative stress-related substrates, and molecules in endocrine and metabolic cascades. We further touch on cross-talk among these systems and comment on the utility of animal models in charting the developmental progression and interaction of these substrates. Based on this comprehensive information, we propose a framework for SZ research based on the hypothesis of an imbalance in homeostatic signaling from immune/inflammatory, oxidative stress, endocrine and metabolic cascades that, at least in part, underlies deficits in neural connectivity relevant to SZ. Thus, this review aims to provide information that is translationally useful and complementary to pathogenic hypotheses that have emerged from genetic studies. Based on such advances in SZ research, it is highly expected that we will discover biomarkers that may help in the early intervention, diagnosis or treatment of SZ.

Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice.

NMDA glutamate receptors have key roles in brain development, function and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal- and forebrain-specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D-serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists.

Growth hormone and proopiomelanocortin are targeted by autoantibodies in a patient with biopsy-proven IgG4-related hypophysitis.

Hypophysitis is a chronic inflammation of the pituitary gland often caused by autoimmunity. Among the autoimmune diseases it is one of the few where the autoantigens remain to be identified. The goal of the paper was to characterize the antigenic profile in a previously reported patient with IgG4-related hypophysitis. Immunofluorescence and immunoblotting were performed to detect antibodies to human pituitary proteins. The proteins recognized by western blotting were then submitted to mass spectrometry for sequencing. The patient's autoantibodies recognized two unique bands around 40 and 30 kDa on immunoblotting. Sequencing revealed one peptide from proopiomelanocortin in the 40 kDa band and four peptides from growth hormone in the 30 kDa band. This work represents the first antigenic profile in IgG4-related hypophysitis, and the first recognition of proopiomelanocortin as a possible pituitary autoantigen. In addition, the work supports previous suggestions of growth hormone as a pituitary autoantigen. Further studies are needed to prove the pathogenicity and diagnostic utility of these two pituitary proteins.

Application of innate immune molecules for a new class of drugs: infection, inflammation and beyond.

The innate immune system plays an important role systemically and locally in infectious and inflammatory diseases. Vaccines, vaccine adjuvants and anti-inflammatory drugs were developed by understanding mechanisms of the innate immune system and causative factors of infection and inflammatory diseases. Pattern-recognition receptors, such as Toll-like receptors, retinoic acid-inducible gene I (RIG-I)-like helicases and nucleotide-binding oligomerization domain(NOD)-like receptors, and their downstream signals have great potential as targets of therapeutics because they are involved in numerous diseases. Furthermore, proteolytic systems such as autophagy and immunoproteasomes play important roles in the innate immune system, making them potential therapeutic targets also. By taking advantage of the immune system, humankind has made a great effort to develop new therapeutic and preventive medicines. Accordingly, we have reported several studies on the development of vaccines and adjuvants based on novel mechanistic strategies. Additionally, we have elucidated the mechanism underlying an interaction between innate immunity and the endocrine system. This review introduces the possible use of innate immune molecules for the development of immunomodulatory drugs and the involvement of the immune system in endocrine metabolic diseases to discuss future applications of innate immune molecules to therapeutics of various inflammatory diseases.