Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The startle reflex is a contraction of the skeletal and facial musculature in response to an intense sensory stimulus. While the 'primary' neural control of startle involves brain structures at, or below, the level of the mesencephalon, the startle reflex (SR) exhibits several forms of plasticity that are modulated by the forebrain. Sensorimotor gating of the SR occurs when the reflex is inhibited by a weak 'pre-pulse' that occurs 30-500 ms prior to the startling stimulus. Since 'pre-pulse inhibition' (PPI) of startle may be impaired in certain psychiatric and neurologic disorders (e.g. schizophrenia, schizotypal personality disorder and Huntington's disease), there has been considerable interest in determining the neural substrates of this form of startle plasticity. In rats, PPI is modulated by neural elements linking the limbic cortex with the striatum and pallidum. These substrates may include hippocampal glutamate efferents to the ventral striatum and striatal GABAergic efferents to the ventral pallidum. The striatal dopaminergic modulation of PPI appears to involve primarily D2, but not D1, receptors. Pallidal efferents may impinge directly on the 'primary' startle circuitry via projections to the mesencephalon or, indirectly, via projections to the thalamus. Evidence is reviewed for other neurochemical substrates of PPI-including acetylcholine and opiates. Sensorimotor gating of the startle reflex appears to have a discrete and identifiable set of neural substrates that may be important for our understanding of neuropsychiatric disorders characterized by deficient suppression or 'gating' of sensory, cognitive or motor processes.
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PMID:The neural substrates of sensorimotor gating of the startle reflex: a review of recent findings and their implications. 2229 49

Crosstalk between G protein-coupled receptors (GPCRs) is one of the key mechanisms used by the cell for integrating multiple signaling pathways. Functional crosstalk at the level of signaling pathways was initially thought to regulate receptor function. Importantly, the existence of GPCR heteromers demonstrates that direct physical interactions between GPCRs could also be behind the crosstalk phenomenon. Neurological disorders such as Parkinson's disease (PD) and schizophrenia have been linked to a dysfunctional communication between certain GPCRs. In this review, we discuss functional and physical crosstalk of the main GPCR families involved in the aforementioned disorders. In addition, we analyze the available structural information on physical crosstalk and highlight some strategies in drug discovery based on these crosstalk mechanisms.
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PMID:Crosstalk within GPCR heteromers in schizophrenia and Parkinson's disease: physical or just functional? 2230 49

Inflammation is increasingly recognized as being of both physiological and pathological importance in the immature brain. The rationale of this review is to present an update on this topic with focus on long-term consequences of inflammation during childhood and in adults. The immature brain can be exposed to inflammation in connection with viral or bacterial infection during pregnancy or as a result of sterile central nervous system (CNS) insults. Through efficient anti-inflammatory and reparative processes, inflammation may resolve without any harmful effects on the brain. Alternatively, inflammation contributes to injury or enhances CNS vulnerability. Acute inflammation can also be shifted to a chronic inflammatory state and/or adversely affect brain development. Hypothetically, microglia are the main immunocompetent cells in the immature CNS, and depending on the stimulus, molecular context, and timing, these cells will acquire various phenotypes, which will be critical regarding the CNS consequences of inflammation. Inflammation has long-term consequences and could speculatively modify the risk of a variety of neurological disorders, including cerebral palsy, autism spectrum disorders, schizophrenia, multiple sclerosis, cognitive impairment, and Parkinson disease. So far, the picture is incomplete, and data mostly experimental. Further studies are required to strengthen the associations in humans and to determine whether novel therapeutic interventions during the perinatal period can influence the occurrence of neurological disease later in life.
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PMID:Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. 2233 91

The microRNA (miRNA) class of non-coding RNAs exhibit a diverse range of regulatory roles in neuronal functions that are conserved from lower vertebrates to primates. Disruption of miRNA expression has compellingly been linked to pathogenesis in neuropsychiatric and neurodegenerative disorders, such as schizophrenia, Alzheimer's disease, and autism. The list of transcript targets governed by a single miRNA provide a molecular paradigm applicable for therapeutic intervention. Indeed, reports have shown that specific manipulation of a miRNA in cell or animal models can significantly alter phenotypes linked with neurological disease. Here, we review how a diverse range of biological systems, including Drosophila, rodents, and primates such as monkeys and humans, can be integrated into the translation of miRNAs as novel clinical targets.
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PMID:The Path to microRNA Therapeutics in Psychiatric and Neurodegenerative Disorders. 2262 84

Homeostatic synaptic scaling in response to neuronal stimulus or activation, and due to changes in cellular niche, is an important phenomenon for memory consolidation, retrieval, and other similar cognitive functions (Turrigiano and Nelson, 2004). Neurological disorders and cognitive disabilities in autism, Rett syndrome, schizophrenia, dementia, etc., are strongly correlated to alterations in protein expression (both synaptic and cytoplasmic; Cajigas et al., 2010). This correlation suggests that efficient temporal regulation of synaptic protein expression is important for synaptic plasticity. In addition, equilibrium between mRNA processing, protein translation, and protein turnover is a critical sensor/trigger for recording synaptic information, normal cognition, and behavior (Cajigas et al., 2010). Thus a regulatory switch, which controls the lifespan, maturation, and processing of mRNA, might influence cognition and adaptive behavior. Here, we propose a two part novel hypothesis that methylation might act as this suggested coordinating switch to critically regulate mRNA maturation at (1) the pre-transcription level, by regulating precursor-RNA processing into mRNA, via other non-coding RNAs and their influence on splicing phenomenon, and (2) the post-transcription level by modulating the regulatory functions of ribonucleoproteins and RNA binding proteins in mRNA translation, dendritic translocation as well as protein synthesis and synaptic turnover. DNA methylation changes are well recognized and highly correlated to gene expression levels as well as, learning and memory; however, RNA methylation changes are recently characterized and yet their functional implications are not established. This review article provides some insight on the intriguing consequences of changes in methylation levels on mRNA life-cycle. We also suggest that, since methylation is under the control of glutathione anti-oxidant levels (Lertratanangkoon et al., 1997), the redox status of neurons might be the central regulatory switch for methylation-based changes in mRNA processing, protein expression, and turnover. Lastly, we also describe experimental methods and techniques which might help researchers to evaluate the suggested hypothesis.
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PMID:Role of a redox-based methylation switch in mRNA life cycle (pre- and post-transcriptional maturation) and protein turnover: implications in neurological disorders. 2274 Aug 13

The blood-brain barrier, a unique feature of the cerebral vasculature, is gaining attention as a feature in common neurologic disorders including stroke, traumatic brain injury, epilepsy, and schizophrenia. Although acute blood-brain barrier dysfunction can induce cerebral edema, seizures, or neuropsychiatric symptoms, epileptogenesis and cognitive decline are among the chronic effects. The mechanisms underlying blood-brain barrier dysfunction are diverse and may range from physical endothelial damage in traumatic brain injury to degradation of extracellular matrix proteins via matrix metalloproteinases as part of an inflammatory response. Clinically, blood-brain barrier dysfunction is often detected using contrast-enhanced imaging. However, these techniques do not give any insights into the underlying mechanism. Elucidating the specific pathways of blood-brain barrier dysfunction at different time points and in different brain diseases using novel imaging techniques promises a more accurate blood-brain barrier terminology as well as new treatment options and personalized treatment.
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PMID:Blood-brain barrier dysfunction in brain diseases: clinical experience. 2313 90

Gene therapy has become of increasing interest in clinical neurosurgery with the completion of numerous clinical trials for Parkinson disease, Alzheimer disease, and pediatric genetic disorders. With improved understanding of the dysfunctional circuitry mediating various psychiatric disorders, deep brain stimulation for refractory psychiatric diseases is being increasingly explored in human patients. These factors are likely to facilitate development of gene therapy for psychiatric diseases. Because delivery of gene therapy agents would require the same surgical techniques currently being employed for deep brain stimulation, neurosurgeons are likely to lead the development of this field, as has occurred in other areas of clinical gene therapy for neurologic disorders. We review the current state of gene therapy for psychiatric disorders and focus specifically on particular areas of promising research that may translate into human trials for depression, drug addiction, obsessive-compulsive disorder, and schizophrenia. Issues that are relatively unique to psychiatric gene therapy are also discussed.
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PMID:Gene therapy for psychiatric disorders. 2326 95

MicroRNA are small RNAs that provide specificity for the RNA induced silencing complex, which forms the basis of an exquisite combinatorial system for posttranscriptional regulation. This system, essential for complex metazoans, is exemplified in the development of the cerebral cortex. To explore the complexity of human cortical miRNA expression in detail, we analyzed RNA from postmortem prefrontal cortex from 97 subjects aged 2 months to 78 years using miRNA microarray. Global miRNA expression was highest in the early years before declining significantly after adolescence (n = 140 decreased, n = 32 increased). Late adolescence was also marked by an inflection point between miRNA on an upward trajectory vs the majority going down. Functional annotation of target genes displaying inverse mRNA expression patterns in the same tissue were overrepresented in neurodevelopmentally significant pathways including neurological disease (most significantly schizophrenia), nervous system development, and cell-to-cell signaling. As mature miRNA expression is largely posttranscriptionally regulated, miRNA biogenesis gene expression was also examined. Dicer and Exportin-5 displayed significant associations with age; however, neither correlated with global miRNA expression across the lifespan. This investigation of cortical miRNA expression provides a framework for understanding the complex posttranscriptional regulatory environment during development and aging that may form a substrate for changes observed in neurodevelopmental disorders.
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PMID:Maturation of the human dorsolateral prefrontal cortex coincides with a dynamic shift in microRNA expression. 2337 13

The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease.
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PMID:Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring. 2345 Nov 23

N-methyl-D-aspartate (NMDA) receptors are important excitatory receptors which contribute to many brain functions. Altered NMDA receptor levels cause maldevelopment of corticostriatal and corticolimbic pathways, which is a neurobiological predisposing factor for development of epilepsy, schizophrenia and other idiopathic psychotic disorders. It was hypothesized that prenatal stress could play a role in pathophysiology of these disorders by affecting expression of the receptors through releasing corticosterone. Sixty-eight virgin female Wistar rats were selected and mated with male rats with the same genotype. Then, the pregnant rats were subjected to restraint or predator stress on 15th, 16th and 17th gestation days. Prenatal stress consisted of restraint or predator stresses of the dams under normal room conditions. After parturition, the pups were studied in terms of density of NMDA receptors in brain at different time points. Meanwhile, blood sample was obtained and corticosterone blood level (CBL) was measured. The pups were then compared with the pups born to unstressed dams. Stress induced significant rise in CBL and NMDA receptors in brain of the offspring. CBL was significantly higher among the stressed rats compared to the control ones; there was significant difference between the two stresses and between the two sexes. The male pups were affected more severely. Stressful events during gestation had important effects on NMDA receptors of the offspring. It can be concluded that stress-induced elevation of NMDA receptors and corticosterone might mediate altered susceptibility to epilepsy and decrease ability of learning and memory and other stress-induced neurologic disorders.
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PMID:Effect of prenatal stress on density of NMDA receptors in rat brain. 2412 Aug 77


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