Current Molecular Medicine (v.15, #2)
Editorial (Thematic Issue: Microphenotypes of Mental Disorders: A Systematic Approach to Study Disease Mechanisms) by Akira Sawa, Satoshi Kida, Kazutaka Ikeda (109-110).
Microendophenotypes of Psychiatric Disorders: Phenotypes of Psychiatric Disorders at the Level of Molecular Dynamics, Synapses, Neurons, and Neural Circuits by S. Kida, T. Kato (111-118).
Psychiatric disorders are caused not only by genetic factors but also by complicated factors such as environmental ones. Moreover, environmental factors are rarely quantitated as biological and biochemical indicators, making it extremely difficult to understand the pathological conditions of psychiatric disorders as well as their underlying pathogenic mechanisms. Additionally, we have actually no other option but to perform biological studies on postmortem human brains that display features of psychiatric disorders, thereby resulting in a lack of experimental materials to characterize the basic biology of these disorders. From these backgrounds, animal, tissue, or cell models that can be used in basic research are indispensable to understand biologically the pathogenic mechanisms of psychiatric disorders. In this review, we discuss the importance of microendophenotypes of psychiatric disorders, i.e., phenotypes at the level of molecular dynamics, neurons, synapses, and neural circuits, as targets of basic research on these disorders.
Impaired DNA Damage Repair as a Common Feature of Neurodegenerative Diseases and Psychiatric Disorders by H. Shiwaku, H. Okazawa (119-128).
Impaired DNA damage repair is a common pathological endophenotype of some types of neurodegenerative diseases, intellectual disabilities, and psychiatric diseases. Dysfunctional DNA repair and DNA damage, including DNA double-stranded breaks, are linked to transcriptional dysfunction and abnormal DNA methylation. Impaired DNA repair in neural stem cells leads to microcephaly or cerebellar ataxia. Furthermore, DNA repair defects and DNA damage in mature neurons lead to progressive cognitive impairment, which might be a common feature of Alzheimer's disease, Huntington’s disease, and other polyglutamine diseases. Oxidative DNA damage and altered DNA repair gene expression are observed in GABAergic neurons in schizophrenia. These findings indicate that impaired DNA repair is a common pathological endophenotype of neurological diseases, and that DNA damage might lead to diverse disease symptoms dependent on timing and the affected cell type.
Neurogenesis and Sensorimotor Gating: Bridging a Microphenotype and an Endophenotype by N. Osumi, N. Guo, M. Matsumata, K. Yoshizaki (129-137).
Human genetic data on psychiatric disorders repeatedly demonstrate the involvement of various genes that are associated with neural development and neurogenesis. Neurogenesis is a biological process that is critical in brain development and continues throughout life. Neurogenesis is a multi-step process starting from the division of neural stem cells/progenitor cells, leading to self-renewal and simultaneously to the production of lineage-committed cells, including neurons and glial cells. Minor defects in the neurogenesis process, such as production of fewer new neurons and malformation of neural circuits, could represent phenotypes of psychiatric disorders at molecular and cellular levels in animal models (here termed as “microphenotypes”). However, microphenotypes are not easily used as biomarkers. We have focused on a physiological condition, sensorimotor gating deficits, that can be scored by a prepulse inhibition (PPI) test. Impaired PPI is considered to be one of the compelling endophenotypes (biological markers) of mental disorders such as schizophrenia, autism, and other neurodevelopmental disorders. Because the neural circuit for PPI involves the hippocampus, a unique brain region where neurogenesis occurs postnatally, we hypothesize that an impairment of preadolescent neurogenesis is critical for the onset of sensorimotor gating defects. To test this hypothesis, we investigated a critical period of neurogenesis that can affect PPI. In this paradigm, we introduced an enriched environment to restore neurogenesis, thereby recovering PPI deficits in mice. We noted impairments in the maturation of newborn neurons in the hippocampal dentate gyrus (DG) and GABAergic neurons in the hippocampus, which could be considered as microphenotypes associated with PPI defects. More precise genetically controlled neurogenesis models (with precise time points or periods) are needed to be studied in further investigation to support our hypothesis.
Clinical Utility of Neuronal Cells Directly Converted from Fibroblasts of Patients for Neuropsychiatric Disorders: Studies of Lysosomal Storage Diseases and Channelopathy by S. Kano, M. Yuan, R.A. Cardarelli, G. Maegawa, N. Higurashi, M. Gaval-Cruz, A.M. Wilson, C. Tristan, M.A. Kondo, Y. Chen, M. Koga, C. Obie, K. Ishizuka, S. Seshadri, R. Srivastava, T.A. Kato, Y. Horiuchi, T.W. Sedlak, Y. Lee, J.L. Rapoport, S. Hirose, H. Okano, D. Valle, P. O'Donnell, A. Sawa, M. Kai (138-145).
Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.
Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders by R. Gao, P. Penzes (146-167).
Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provi de essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.
Imaging Genetics and Psychiatric Disorders by R. Hashimoto, K. Ohi, H. Yamamori, Y. Yasuda, M. Fujimoto, S. Umeda-Yano, Y. Watanabe, M. Fukunaga, M. Takeda (168-175).
Imaging genetics is an integrated research method that uses neuroimaging and genetics to assess the impact of genetic variation on brain function and structure. Imaging genetics is both a tool for the discovery of risk genes for psychiatric disorders and a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative and mechanistic aspects of brain function implicated in psychiatric disease. Early studies of imaging genetics included association analyses between brain morphology and single nucleotide polymorphisms whose function is well known, such as catechol-Omethyltransferase (COMT) and brain-derived neurotrophic factor (BDNF). GWAS of psychiatric disorders have identified genes with unknown functions, such as ZNF804A, and imaging genetics has been used to investigate clues of the biological function of these genes. The difficulty in replicating the findings of studies with small sample sizes has motivated the creation of largescale collaborative consortiums, such as ENIGMA, CHARGE and IMAGEN, to collect thousands of images. In a genome-wide association study, the ENIGMA consortium successfully identified common variants in the genome associated with hippocampal volume at 12q24, and the CHARGE consortium replicated this finding. The new era of imaging genetics has just begun, and the next challenge we face is the discovery of small effect size signals from large data sets obtained from genetics and neuroimaging. New methods and technologies for data reduction with appropriate statistical thresholds, such as polygenic analysis and parallel independent component analysis (ICA), are warranted. Future advances in imaging genetics will aid in the discovery of genes and provide mechanistic insight into psychiatric disorders.
Decoupling of N-Acetyl-Aspartate and Glutamate Within the Dorsolateral Prefrontal Cortex in Schizophrenia by J.M. Coughlin, T. Tanaka, A. Marsman, H. Wang, S. Bonekamp, P.K. Kim, C. Higgs, M. Varvaris, R.A.E. Edden, M. Pomper, D. Schretlen, P.B. Barker, A. Sawa (176-183).
Aberrant function of glutamatergic pathways is likely to underlie the pathology of schizophrenia. Evidence of oxidative stress in the disease pathology has also been reported. N-Acetylaspartate (NAA) is metabolically linked to both cascades and may be a key marker in exploring the interconnection of glutamatergic pathways and oxidative stress. Several studies have reported positive correlation between the levels of NAA and Glx (the sum of glutamate and glutamine) in several brain regions in healthy subjects, by using proton magnetic resonance spectroscopy ([1H]MRS). Interestingly, one research group recently reported decoupling of the relationship between NAA and Glx in the hippocampus of patients with schizophrenia. Here we report levels of NAA and Glx measured using [1H]MRS, relative to the level of creatine (Cr) as an internal control. The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in 25 patients with schizophrenia and 17 matched healthy controls were studied. In DLPFC, NAA/Cr and Glx/Cr were significantly positively correlated in healthy controls after correction for the effect of age and smoking status and after correction for multiple comparisons (r= 0.627, P= 0.017). However, in patients with schizophrenia, the positive correlation between NAA/Cr and Glx/Cr was not observed even after correcting for these two variables (r= -0.330, P= 0.124). Positive correlation between NAA/Cr and Glx/Cr was not observed in the ACC in both groups. Decoupling of NAA and Glx in the DLPFC may reflect the interconnection of glutamatergic pathways and oxidative stress in the pathology of schizophrenia, and may possibly be a biomarker of the disease.
How Does Pain Induce Negative Emotion—Role of the Bed Nucleus of the Stria Terminalis in Pain-Induced Place Aversion by M. Minami, S. Ide (184-190).
Pain consists of sensory-discriminative and negative-affective components. Neuronal mechanisms for the sensory component of pain have been investigated extensively. On the other hand, neuronal mechanisms for the affective component of pain remain to be investigated. Recent behavioral studies have revealed the brain regions and neuronal mechanisms involved in the affective component of pain. Glutamatergic transmission within the anterior cingulate cortex and basolateral amygdaloid nucleus plays a critical role in pain-induced aversion. Noradrenaline and corticotropin-releasing factor (CRF) within the ventral and dorsolateral parts of the bed nucleus of the stria terminalis (BNST), respectively, play important roles in paininduced aversion. Electrophysiological studies have revealed that both noradrenaline and CRF activate type II BNST neurons, which may inhibit the BNST output neurons. A recent histochemical study showed that most VTA-projecting BNST output neurons are GABAergic neurons, which preferentially make synaptic contact with VTA GABAergic neurons. Therefore, activation of VTA-projecting BNST output neurons should increase the neuronal excitability of VTA dopaminergic (DAergic) neurons through increased inhibitory input to VTA GABAergic neurons, which negatively regulate VTA DAergic neurons. Pain-induced release of noradrenaline and CRF within the BNST may activate type II BNST neurons, which could suppress VTA-projecting BNST output neurons, thereby attenuating the excitatory influence to the VTA DAergic neurons. Recent optogenetic studies suggest that the suppression of VTA DAergic neurons is sufficient to induce place aversion. Pain-induced place aversion may be due to the suppression of VTA DAergic neurons via the processing of nociceptive information within the BNST.