Astrocytic and neuronal localization of kynurenine aminotransferase-2 in the adult mouse brain.

During catabolism of tryptophan through the kynurenine (KYN) pathway, several endogenous metabolites with neuromodulatory properties are produced, of which kynurenic acid (KYNA) is one of the highest significance. The causal role of altered KYNA production has been described in several neurodegenerative and neuropsychiatric disorders (e.g., Parkinson's disease, Huntington's disease, schizophrenia) and therefore kynurenergic manipulation with the aim of therapy has recently been proposed. Conventionally, KYNA is produced from its precursor L-KYN with the aid of the astrocytic kynurenine aminotransferase-2 (KAT-2) in the murine brain. Although the mouse is a standard therapeutic research organism, the presence of KAT-2 in mice has not been described in detail. This study demonstrates the presence of kat-2 mRNA and protein throughout the adult C57Bl6 mouse brain. In addition to the former expression data from the rat, we found prominent KAT-2 expression not only in the astrocyte, but also in neurons in several brain regions (e.g., hippocampus, substantia nigra, striatum, and prefrontal cortex). A significant number of the KAT-2 positive neurons were positive for GAD67; the presence of the KAT-2 enzyme we could also demonstrate in mice brain homogenate and in cells overexpressing recombinant mouse KAT-2 protein. This new finding attributes a new role to interneuron-derived KYNA in neuronal network operation. Furthermore, our results suggest that the thorough investigation of the spatio-temporal expression pattern of the relevant enzymes of the KYN pathway is a prerequisite for developing and understanding the pharmacological and transgenic murine models of kynurenergic manipulation.

Gender-Specific Degeneration of Dementia-Related Subcortical Structures Throughout the Lifespan.

Age-related changes in brain structure are a question of interest to a broad field of research. Structural decline has been consistently, but not unambiguously, linked to functional consequences, including cognitive impairment and dementia. One of the areas considered of crucial importance throughout this process is the medial temporal lobe, and primarily the hippocampal region. Gender also has a considerable effect on volume deterioration of subcortical grey matter (GM) structures, such as the hippocampus. The influence of age×gender interaction on disproportionate GM volume changes might be mediated by hormonal effects on the brain. Hippocampal volume loss appears to become accelerated in the postmenopausal period. This decline might have significant influences on neuroplasticity in the CA1 region of the hippocampus highly vulnerable to pathological influences. Additionally, menopause has been associated with critical pathobiochemical changes involved in neurodegeneration. The micro- and macrostructural alterations and consequent functional deterioration of critical hippocampal regions might result in clinical cognitive impairment-especially if there already is a decline in the cognitive reserve capacity. Several lines of potential vulnerability factors appear to interact in the menopausal period eventually leading to cognitive decline, mild cognitive impairment, or Alzheimer's disease. This focused review aims to delineate the influence of unmodifiable risk factors of neurodegenerative processes, i.e., age and gender, on critical subcortical GM structures in the light of brain derived estrogen effects. The menopausal period appears to be of key importance for the risk of cognitive decline representing a time of special vulnerability for molecular, structural, and functional influences and offering only a narrow window for potential protective effects.

Schizophrenia as a disorder of molecular pathways.

Over the last decade, transcriptome studies of postmortem tissue from subjects with schizophrenia revealed that synaptic, mitochondrial, immune system, gamma-aminobutyric acidergic, and oligodendrocytic changes are all integral parts of the disease process. The combined genetic and transcriptomic studies argue that the molecular underpinnings of the disease are even more varied than the symptomatic diversity of schizophrenia. Ultimately, to decipher the pathophysiology of human disorders in general, we will need to understand the function of hundreds of genes and regulatory elements in our genome and the consequences of their overexpression and reduced expression in a developmental context. Furthermore, integration of knowledge from various data sources remains a monumental challenge that has to be systematically addressed in the upcoming decades. In the end, our success in interpreting the molecular changes in schizophrenia will depend on our ability to understand the biology using innovative ideas and cannot depend on the hope of developing novel, more powerful technologies.

Immune system disturbances in schizophrenia.

Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease, and it is likely that these immune changes actively contribute to disease symptoms. Gene expression disturbances in the brain of subjects with schizophrenia show complex, region-specific changes with consistently replicated and potentially interdependent induction of serpin peptidase inhibitor, clade A member 3 (SERPINA3) and interferon inducible transmembrane protein (IFITM) family transcripts in the prefrontal cortex. Recent data suggest that IFITM3 expression is a critical mediator of maternal immune activation. Because the IFITM gene family is primarily expressed in the endothelial cells and meninges, and because the meninges play a critical role in interneuron development, we suggest that these two non-neuronal cell populations might play an important role in the disease pathophysiology. Finally, we propose that IFITM3 in particular might be a novel, appealing, knowledge-based drug target for treatment of schizophrenia.

The role of cannabinoid 1 receptor expressing interneurons in behavior.

Schizophrenia is a devastating neurodevelopmental disorder that affects approximately 1% of the population. Reduced expression of the 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of the disease and is encoded by the GAD1 gene. In schizophrenia, GAD67 downregulation occurs in multiple interneuronal subpopulations, including the cannabinoid receptor type 1 positive (CNR1+) cells, but the functional consequences of these disturbances are not well understood. To investigate the role of the CNR1-positive GABA-ergic interneurons in behavioral and molecular processes, we employed a novel, miRNA-mediated transgenic mouse approach. We silenced the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Cnr1 bacterial artificial chromosome. Behavioral characterization of our transgenic mice showed elevated and persistent conditioned fear associated with an auditory cue and a significantly altered response to an amphetamine challenge. These deficits could not be attributed to sensory deficits or changes in baseline learning and memory. Furthermore, HPLC analyses revealed that Cnr1/Gad1 mice have enhanced serotonin levels, but not dopamine levels in response to amphetamine. Our findings demonstrate that dysfunction of a small subset of interneurons can have a profound effect on behavior and that the GABA-ergic, monoamine, and cannabinoid systems are functionally interconnected. The results also suggest that understanding the function of various interneuronal subclasses might be essential to develop knowledge-based treatment strategies for various mental disorders including schizophrenia and substance abuse.

The Iowa Gambling Task in depression - what have we learned about sub-optimal decision-making strategies?

Our earlier study found patients with depression to show a preference for larger reward as measured by the Iowa Gambling Task (IGT). In this IGT version, larger rewards were associated with even larger consequent losses. In the light of the clinical markers defining depressive disorder, this finding might appear controversial at first. Performance of depressed patients on various decision-making (DM) tasks is typically found to be impaired. Evidence points toward reduced reward learning, as well as the difficulty to shift strategy and integrate environmental changes into DM contingencies. This results in an impaired ability to modulate behavior as a function of reward, or punishment, respectively. Clinical symptoms of the disorder, the genetic profile, as well as personality traits might also influence DM strategies. More severe depression increased sensitivity to immediate large punishment, thus predicting future decisions, and was also associated with higher harm avoidance. Anhedonic features diminished reward learning abilities to a greater extent, even predicting clinical outcome. Several questions about how these aspects relate remain to be clarified. Is there a genetic predisposition for the DM impairment preceding mood symptoms? Is it the consequence of clinical signs or even learned behavior serving as a coping strategy? Are patients prone to develop an aversion of loss or are they unable to sense or deal with reward or the preference of reward? Does the DM deficit normalize or is a persisting impairment predictor for clinical outcome or relapse risk? To what extent is it influenced by medication effects? How does a long-lasting DM deficit affect daily life and social interactions? Strikingly, research evidence indicates that depressed patients tend to behave less deceptive and more self-focused, resulting in impaired social DM. The difficulty in daily interpersonal interactions might contribute to social isolation, further intensifying depressive symptoms.

Increased axonal expression of nectin-1 in multiple sclerosis plaques.

Nectin-1 is a cell adhesion molecule that plays a role in interneuronal synapse formation, in axonal guidance during development and possibly in neuron-glia interactions. To better understand axonal changes in MS, nectin-1 expression was determined by immunohistochemistry in normal adult human cerebral white matter (n = 4) and in six MS plaques (three active and three inactive). The intensity of axonal nectin-1 expression was scored on a scale of 0 to 4+. In normal adult cerebral white matter, axons showed weak nectin-1 expression with a score of 1.25 ± 0.50. Axonal nectin-1 expression was significantly stronger within both active (score = 3.33 ± 0.289, p = 0.001) and inactive (score = 2.16 ± 0.29, p = 0.038) MS plaques than in normal white matter. Axons in white matter adjacent to MS plaques showed nectin-1 expression (score = 1.5 ± 0.50) that was not statistically different from normal controls (p = 0.542). These findings raise the possibility that increased expression of nectin-1 in MS lesions plays a role in the pathogenesis of MS through participation in axonal responses to injury and mediation of altered neuron-glia interactions relevant to myelination.

Personality traits and coping compensate for disadvantageous decision-making in long-term alcohol abstinence.

AIMS: High relapse rate and extreme difficulty to maintain abstinence are core characteristics of alcohol dependence (AD). Previous studies have demonstrated a persistent decision-making (DM) deficit in AD. We aimed to reveal specific personality features and stress-coping mechanisms presumed to compensate for ineffective DM skills. METHODS: Eighty-eight unmedicated patients with AD were enrolled. Intact general cognitive status was assured by IQ above 90. Forty-three patients had an average abstinence period of 12 weeks and were currently in an inpatient treatment program (short-term abstinence group, STA) and 45 patients were abstinent for at least 3 years (long-term abstinence group, LTA). The two groups were assessed using an integrative approach combining domains of DM, temperament and character dimensions and stress-coping measures. RESULTS: Both groups performed at chance level with no linear improvement tendency on the gambling task assessing DM adequacy. The LTA group scored significantly higher on scales of self-directedness and cooperativeness. In contrast, levels of harm avoidance, emotion-oriented coping and perceived stress were significantly higher in the STA group. CONCLUSION: Our findings provide new evidence for a persistent DM deficit with no learning effect in AD. Despite the deficit, alcohol-dependent patients can achieve LTA. STA patients perceive higher levels of stress and use non-adaptive coping strategies. We propose that the more adaptive personality profile of LTA patients contributes to the compensation of the trait-like DM deficit in alcoholism. These compensatory features represent promising new targets for preventive measures and therapeutic interventions in AD.

[Schizophrenia, environment and epigenetics]. / Szkizofrénia, környezet és epigenetika.

Psychotic, cognitive and affective symptoms defining schizophrenia may, though much less severe, manifest themselves in up to 10 to 20% of the general population. What explains the fact that in certain cases the symptoms require even constant medical supervision, while others are capable of living a normal life within social conventions? Which factors lead to the transition of mild, subclinical manifestations and vulnerability indicators towards the outburst of one of the most severe and depriving mental disorders? Genetic susceptibility is undoubtedly crucial. More recent research findings emphasize the modifying effect of specific environmental factors on gene expression. The gene-environment interplay may induce so-called epigenetic alterations which may manifest themselves over several generations. Future integrative, multi-dimensional and flexible schizophrenia research approaches focusing on the identification of neurobiological and cognitive outcomes are much needed to understand disease vulnerability, susceptibility mechanisms, periods and interactions. Research methods may differ, but our aim is common - establishing more effective diagnostic and therapeutic interventions.

Anesthesia for electroconvulsive therapy in early pregnancy.

Pharmacological treatment of major psychiatric conditions (eg, schizophrenia, bipolar disorder) is exceptionally difficult during pregnancy. Despite all efforts, medication-resistant life-threatening mental deterioration can emerge with the urgent need for rapid and effective intervention. In these cases, electroconvulsive therapy (ECT) may represent the only valid and safe therapeutic option. Here, we present the challenging medical case of a 31-year-old primigravida with a general medical history of obesity and hypertension, previously diagnosed with bipolar affective disorder, now presenting with severe, therapy-resistant manic agitation. Full symptomatic remission was achieved and preserved with ECT given between the 7th and 22nd gestational weeks, the pregnancy reached full term, and a healthy child was born by cesarean delivery performed because of preeclampsia. Although it is unusual to start ECT this early in pregnancy, with the thorough assessment of potential risk factors and preventive measures taken, it can be the most effective and presumably the least risky treatment approach. By delineating key aspects of both the psychiatric and anesthetic management of this case, we aim to highlight the importance of a close cooperation between all medical fields involved in clinical practice.

Tau haplotypes and ApoE4 do not act in synergy on Alzheimer's disease.

There are conflicting results regarding the role of tau (MAPT) haplotypes in neurodegenerative disorders. Recent reports suggest that ethnicity factors and gene-gene interactions may influence the risk of developing Alzheimer's disease (AD). The present study investigates possible synergism between MAPT haplotype and ApoE state in Hungarian Caucasian AD cases (n=91) and control (n=83) population. The difference in MAPT H1 allele frequency did not reach significant level in AD (78%), and control individuals (73.5%), however ApoE4 carriers were significantly overrepresented in AD (34.1% vs. 20%) compared to the control population. Though a specific combination of ApoE4 and H1 alleles were found to be associated to AD (14.5% vs. 30.8%), synergistic genetic interaction could not be inferred. Our findings support the notion that while ApoE4 might be involved in AD pathology the MAPT H1 allele neither associates nor interacts through an epistasis with ApoE4 in the development of the disease.

Analyzing schizophrenia by DNA microarrays.

To understand the pathological processes of schizophrenia, we must embrace the analysis of the diseased human brain: we will never be able to recapitulate the pathology of uniquely human disorders in an animal model. Based on the outcome of the transcriptome profiling experiments performed to date, it appears that schizophrenia is associated with a global gene expression disturbance across many cortical regions. In addition, transcriptome changes are present in multiple cell types, including specific subclasses of principal neurons, interneurons, and oligodendrocytes. Furthermore, transcripts related to synaptic transmission, energy metabolism, and inhibitory neurotransmission are routinely found underexpressed in the postmortem brain tissue of subjects with schizophrenia. To put these transcriptome data in biological context, we must make our data publicly available and report our findings in a proper, expanded Minimum Information About a Microarray Experiment format. Cell-type specific expression profiling and sequencing-based transcript assessments should be expanded, with particular attention to understanding splice-variant changes in various mental disorders. Deciphering the pathophysiology of mental disorders depends on integrating data from across many research fields and techniques. Leads from postmortem transcriptome profiling will be essential to generate model animals, perform tissue culture experiments, and develop or evaluate novel drugs to treat this devastating disorder.

Infragranular gene expression disturbances in the prefrontal cortex in schizophrenia: signature of altered neural development?

The development of the human neocortex gives rise to a complex cytoarchitecture, grouping together cells with similar structure, connectivity and function. As a result, the six neocortical laminae show distinct molecular content. In schizophrenia, many anatomical and neurochemical changes appear to be restricted to a subset of lamina and/or cell types. In this study, we hypothesized that supragranular (SG; laminae II-III) and infragranular layers (IG; laminae V-VI) of area 46 in the human prefrontal cortex will show distinct and specific transcriptome alterations between subjects with schizophrenia and matched controls. To enhance sample homogeneity, we compared the gene expression patterns of the SG and IG layers of 8 matched middle-aged male subjects with schizophrenia to 8 pairwise matched controls using two replicate DNA microarrays for each sample. The study revealed strong disease-related laminar expression differences between the SG and IG layers. Expression changes were dominated by an overall underexpression of the IG-enriched genes in the schizophrenia subjects compared to normal control subjects. Furthermore, using a diagnosis-blind, unsupervised clustering of the control-derived SG or IG-enriched transcripts, the IG-enriched markers segregated the subjects with schizophrenia from the matched controls with a high degree of confidence. Importantly, multiple members of the semaphorin gene family reported altered gene expression, suggesting that the IG gene expression disturbances in subjects with schizophrenia may be a result of altered cortical development and disrupted brain connectivity.

Epstein-Barr virus encephalitis mimicking clinical and electroencephalographic characteristics of herpes simplex encephalitis.

A rare case of EBV encephalitis initially diagnosed as Herpes simplex infection is presented to highlight the importance of EBV specific intrathecal ELISA and liquor PCR based differential diagnosis when Herpes simplex encephalitis specific clinical symptoms, neuroimaging signs and electroencephalographic features are present. The case report also suggests that acyclovir treatment might be beneficial for the long term outcome in adult EBV encephalitis patients.

[Affective and cognitive decision making in major depression: influence of the prefrontal cortex, serotonin transporter genotype and personality traits]. / Affektív és kognitív döntéshozatali funkciók major depresszióban: a prefrontális cortex, a szerotonintranszporter és a személyiség szerepe.

Patients with major depressive disorder (MDD) show neuropsychological impairments, including deficient executive functions and suboptimal decision-making strategies, which are mediated by several brain regions. In the development of these symptoms the pathology of the prefrontal cortex (PFC), including the dorsolateral, ventromedial and orbitofrontal regions, may also play an important role. Neuropsychological assessment is a useful tool in detecting and measuring these deficiencies, showing that patients with MDD exhibit altered sensitivity to reward and punishment. However, impairment of emotional decision-making strategies in MDD is influenced by genetic variations (5-HTTLPR polymorphism) and personality traits, which seem to have a higher predictive value on decision making performance than the clinical symptoms.

Nectin-1 (HveC) is expressed at high levels in neural subtypes that regulate radial migration of cortical and cerebellar neurons of the developing human and murine brain.

Herpes simplex viruses (HSV) produce age-dependent encephalitis characterized by more severe involvement of the cerebral cortex in younger hosts. To elucidate the potential role of the major neural entry receptor of HSV, nectin-1, in age-dependent susceptibility of cortical neurons to viral encephalitis, the authors examined the anatomical distribution of the receptor protein in the developing human and mouse cerebral cortex, hippocampus, and cerebellum by immunohistochemistry. Nectin-1 is expressed at high levels in guiding cells (radial glial cells and Cajal-Retzius cells) that regulate radial migration of neurons in cortical lamination, at lower levels in migrating neurons, and at variable levels in the transient ventricular and marginal zones of the cerebral cortical wall. These results may have implications regarding the selective spatiotemporal tropism of HSV to specific neuronal populations, and for the better understanding of neurodevelopmental defects caused by fetal HSV infections.

Spatiotemporal changes of the herpes simplex virus entry receptor nectin-1 in murine brain during postnatal development.

Herpes simplex virus (HSV) is known to replicate within the limbic system and to alter behavior in both humans and experimental animals. However, the reason why the virus selectively damages this anatomical, developmental, and functional neural unit remains a mystery. Nor is it known why herpes simplex encephalitis fails to respect these neuroanatomical boundaries in newborns. In the present study, the authors determined the spatiotemporal changes in the distribution of the major neural entry receptor for HSV (nectin-1) in postnatal mouse and rat brains. Discrete nectin-1 immunopositivity was observed in regions susceptible to HSV infection in specific developmental phases of central nervous system. The authors also describe nectin-1-related pathways controlling neuronal cell migration/brain morphogenesis, the disruption of which might lead to the emergence of mental disorders with a rapid cognitive decline.

Use of a recombinant pseudorabies virus to analyze motor cortical reorganization after unilateral facial denervation.

A unilateral facial nerve injury (n7x) was found to influence the transcallosal spread of the attenuated strain of pseudorabies virus (PRV Bartha) from the affected (left) primary motor cortex (MI) to the contralateral MI of rats. We used Ba-DupLac, a recombinant PRV strain, for the tracing experiments since this virus was demonstrated to exhibit much more restricted transportation kinetics than that of PRV Bartha, and is therefore more suitable for studies of neuronal plasticity. Ba-Duplac injection primarily infected several neurons around the penetration channel, but hardly any transcallosally infected neurons were observed in the contraleral MI. In contrast, after right facial nerve injury, Ba-DupLac was transported from the primarily infected neurons in the left MI to the contralateral side, and resulted in the labeling of several neurons due to a transneuronal infection. These results reveal that a peripheral nerve injury induces changes in the Ba-DupLac infection pattern in the related cortical areas. These findings and the literature data suggest that this phenomenon may be related to the changes in the expression or to the redistribution of cell-adhesion molecules, which are known to facilitate the entrance and/or transmission of PRV into neurons.