Apolipoproteins in the brain: implications for neurological and psychiatric disorders

The brain is the most lipid-rich organ in the body and, owing to the impermeable nature of the blood-brain barrier, lipid and lipoprotein metabolism within this organ is distinct from the rest of the body. Apolipoproteins play a well-established role in the transport and metabolism of lipids within the CNS; however, evidence is emerging that they also fulfill a number of functions that extend beyond lipid transport and are critical for healthy brain function. The importance of apolipoproteins in brain physiology is highlighted by genetic studies, where apolipoprotein gene polymorphisms have been identified as risk factors for several neurological diseases. Furthermore, the expression of brain apolipoproteins is significantly altered in several brain disorders. The purpose of this article is to provide an up-to-date assessment of the major apolipoproteins found in the brain (ApoE, ApoJ, ApoD and ApoA-I), covering their proposed roles and the factors influencing their level of expression. Particular emphasis is placed on associations with neurological and psychiatric disorders.     

Epigenetic regulation of G protein coupled receptor signaling and its implications in psychiatric disorders

G protein-coupled receptors (GPCRs) act as a relay center through which extracellular signals, in the form of neurotransmitters or therapeutics, are converted into an intracellular response, which ultimately shapes the overall response at the tissue and behavioral level. Remarkably in similar ways, epigenetic mechanisms also modulate the expression pattern of a large number of genes in response to the dynamic environment inside and outside of the body, and consequently overall response. Emerging evidences from the pharmacogenomics and preclinical studies clearly suggest that these two distinct mechanisms criss-cross each other in several neurological disorders. At one hand such cross-talks between two distinct mechanisms make disease etiology more challenging to understand, while on the other hand if dealt appropriately, such situations might provide an opportunity to find novel druggable target and strategy for the treatment of complex diseases. In this review article, we have summarized and highlighted the main findings that tie epigenetic mechanisms to GPCR mediated signaling in the pathophysiology of central nervous system (CNS) disorders, including depression, addiction and pain.     

Genetic analysis of psychiatric disorders in humans

Psychiatric disorders place a large burden not only on affected individuals and their families but also on societies and health services. Current treatment is only effective in a proportion of the patients, so considerable effort has been put into the development of new medications. The susceptibility to all major psychiatric disorders is, at least in part, genetic. Knowledge of the genes that underlie this susceptibility may lead to the identification of new drug targets and the development of more effective treatments. Therefore, numerous genetic studies in search for the genes involved in psychiatric disorders have been performed. Although results of both linkage and association studies have been inconsistent, several promising gene regions and candidate genes have been identified recently. In this article, we will review the strategies that proved to be successful in detecting genes for psychiatric disorders and we will provide some recommendations to increase the probability of detecting susceptibility genes in genetic studies of different designs.     

From pharmacotherapy to pathophysiology: emerging mechanisms of apolipoprotein D in psychiatric disorders

Apolipoprotein D (apoD) is an atypical plasma apolipoprotein and, based on its primary structure, it is a member of the lipocalin protein superfamily. Lipocalins have been extensively used as disease markers and, accordingly, apoD has become increasingly recognized as an important factor in the pathology of human neurodegenerative and neuropsychiatric disorders. ApoD expression is increased in the plasma and brains of subjects with schizophrenia and bipolar disorder, suggesting that it acts as a marker for disease pathology. ApoD also exhibits complex regulation by antipsychotic drug treatment and may represent a distinguishing mechanism of typical versus atypical drugs. The precise role of apoD in the CNS and disease remains to be elucidated, but recent findings have suggested that it plays an important role in the regulation of arachidonic acid signaling and metabolism providing further support for phospholipid membrane pathology in schizophrenia.     

Translocator protein (TSPO) and neurosteroids: implications in psychiatric disorders

The translocator protein (TSPO) is a five transmembrane domain protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans. The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders.     

Chloride channels: An emerging molecular picture

Chloride channels are probably found in every cell, from bacteria to mammals. Their physiological tasks range from cell volume regulation to stabilization of the membrane potential, signal transduction, transepithelial transport and acidification of intracellular organelles. These different functions require the presence of many distinct chloride channels, which are differentially expressed and regulated by various stimuli. These include various intracellular messengers (like calcium and cyclic AMP), pH, extracellular ligands and transmembrane voltage. Three major structural classes of chloride channels are known to date, but there may be others not yet identified. After an overview of the general functions of chloride channels, this review will focus on these cloned chloride channels: the CLC chloride channel family, which includes voltage-gated chloride channels, and the cystic fibrosis transmembrane regulator (CFTR), which performs other functions in addition to being a chloride channel. Finally, a short section deals with GABA and glycine receptors. Diseases resulting from chloride channel defects will be specially emphasized, together with the somewhat limited information about how these proteins work at the molecular level.     

Epigenetics and the environment: emerging patterns and implications

Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development.     

Apolipoprotein D modulates arachidonic acid signaling in cultured cells: implications for psychiatric disorders

Deficiencies in arachidonic acid (AA) parameters have been reported in schizophrenic patients. AA is a primary binding ligand for apolipoprotein D (apoD), which is increased in response to antipsychotic drug treatment and elevated in subjects with schizophrenia and bipolar disorder. In this study, we investigated whether apoD might modulate AA signaling/mobilization in cultured embryonic kidney (HEK) 293T cells. Immunofluorescent labeling revealed both cytosolic and membrane-bound expression of apoD protein in apoD-transfected cells. In cells expressing apoD, phorbal 12-myristate 13-acetate-induced AA release was inhibited compared to controls and membrane levels of AA were elevated, as indicated by the amount of AA maximally incorporated into membrane phospholipids. In addition, exogenous apoD added directly to the incubation media prevented cellular uptake of free [3H]AA. These results suggest that apoD acts to stabilize membrane-associated AA by preventing release and sequestering free AA in the cell. These actions of apoD may be beneficial to psychiatric patients.     

Different architectures of the collagen fibril: morphological aspects and functional implications

Several tissues known to contain collagen fibrils with a ‘helical’ arrangement were studied by t.e.m. and freeze-fracture. In all the tissues examined, the diameter of the collagen fibrils appeared to be tissue-specific and fairly constant within the same tissue. No statistical differences, on the contrary, were detectable in the coiling angle which appeared similar in all the tissues and independent of both diameter and age of the fibril. Rat tail tendon was also examined under the same technical conditions and showed collagen fibrils of large and very heterogeneous diameter and with a consistent ‘straight’ arrangement. These data seem to suggest that the ‘helical’ and ‘straight’ arrangements may actually identify different types of collagen fibrils. The authors discuss the possible functional significance of these arrangements and present two hypotheses on the three-dimensional structure of the ‘helical’ fibril.     

Kynurenines: from the perspective of major psychiatric disorders

Psychiatric disorders are documented to be associated with a mild pro-inflammatory state. Pro-inflammatory mediators could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm where excitotoxic N-methyl-D-aspartate receptor agonist quinolinic acid is formed. An unbalanced metabolism in terms of neuroprotective and neurotoxic effects, such as reduced kynurenic acid to kynurenine ratio, has been demonstrated in the major psychiatric disorders such as unipolar depression, bipolar manic-depressive disorder and schizophrenia, and in drug-induced neuropsychiatric side effects such as interferon-α treated patients. The changes in serum or plasma are shown to be associated with central changes such as in the cerebrospinal fluid and certain brain areas. While currently available antidepressants and mood stabilizers could not efficiently improve these neurochemical changes within the same period that could induce clinical improvement, some antipsychotic treatments could reverse certain metabolic imbalances. Some of these changes were tested also in animal models. In this review the role of this unbalanced kynurenine metabolism through interactions with other neurochemicals is discussed as a major contributing pathophysiological mechanism in psychiatric disorders. Moreover, the biomarker role of kynurenine metabolites and future therapeutic opportunities are also discussed.     

Receptor kinase activation and signal transduction in plants: an emerging picture

Plant receptor kinases play key roles in the cell-cell recognition process during development, defense against pathogens, and self incompatibility. Recent identification of potential ligand molecules and downstream signaling components, together with biochemical studies on receptor-complex formation, have revealed an emerging picture of receptor-kinase activation and signal transduction in plants.     

Sigma binding sites in the brain; an emerging concept for multiple sites and their relevance for psychiatric disorders

An increasing amount of evidence suggests the existence of specific binding sites for psychotomimetic drugs from the opiate-benzomorphan and arylcyclohexylamine series. The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine and (+)pentazocine and also for some neuroleptics (e.g., haloperidol). The PCP receptor has preferential affinity for phencyclidine (PCP) analogs and other non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists. The physiological significance of the PCP receptor is associated with the blockade of the NMDA type of the glutamate receptor, implying a neuroprotective role of the PCP receptor. However, the significance of the sigma binding sites is less conspicuous. It is not only that drugs from distinct pharmacological classes display a certain degree of affinity for the "sigma/haloperidol" binding sites, but also that drugs which do not induce or block psychotomimetic activity, i.e., (+)3-(3-hydroxyphenyl)-N-(1-propyl) piperidine [(+)3-PPP] and 1,3-di-o-tolyl-guanidine (DTG), display relatively high affinity for the sigma binding sites. The diversity of the compounds which are proposed to interact with the sigma receptors and the variety of the responses elicited by these drugs suggest the existence of sigma receptor subtypes. The finding that the type A of monoamine oxidase (MAO) inhibitors, which are used in treatment of affective disorders, display high affinity for the sigma binding sites suggests their involvement in affective or schizoaffective disorders. Revealing the existence of sigma receptor subtypes may help to elucidate their association with various psychiatric disorders.     

Genetic variation, its assessment and implications to the conservation of seagrasses

In a study of the widespread Australian endemic seagrass Posidonia australis , allozyme analysis identified a wide range in population genetic structure assessed using the multilocus genotype diversity statistic ( D _G). Values of D _G between zero and one were obtained; however, RAPD analysis generally detected higher levels of diversity, where D _G values were all greater than 0.5 ( D _G = 0.67 – 1). Some populations were allozymically monomorphic using allozyme analysis yet were highly polymorphic using RAPD analysis. The differences observed between methods, particularly among allozymically uniform populations, demonstrate the importance of choosing an appropriate method when assessing genotypic diversity. Different methods may reflect different historical aspects of population processes where allozymes reflect broader-scale gene flow and population establishment and DNA fingerprinting methods such as RAPDs may reflect fine-scale local recruitment events and shorter-term population processes. Using either method alone, particularly in genotypically depauperate organisms such as seagrasses and other clonal organisms, will be problematic in assessing their population genetic potential, a parameter being used by conservation managers to decide upon management strategies in rare and endangered organisms. It is recommended that the impact of disturbance assessed using genotypic diversity measures requires more than one technique to provide the most appropriate information for designing subsequent conservation strategies.     

Physiological regulation-deregulation and psychiatric disorders

This article discusses regulation-deregulation theory, a theory that integrates both old and new concepts to explain behavior-physiology interactions and changes in psychiatric disorder probability. The theory postulates: that specific types and frequencies of social interactions are essential to maintain normal physiological function; when essential interactions fail to occur, atypical physiological states (deregulation) develop; and deregulation is associated with the presence of unpleasant feelings and an increase in the frequency of psychiatric disorders. Implications of the theory are that certain types of social interactions are critical proximate mechanisms in determining the onset of psychiatric disorders, and that social interaction type and frequency, through affecting different physiological systems, alter the course of psychiatric disorders.