Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders.

Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.

Comparison of methohexital and etomidate as anesthetic agents for electroconvulsive therapy in affective and psychotic disorders.

BACKGROUND: ECT is a well-established treatment for severe depression. The available data on psychosis are limited, but reliable. Its therapeutic potential relies on the induction of a generalized seizure. Besides other narcotics, methohexital and etomidate are used for general anesthesia in ECT. Since prolonged seizures have been reported following the use of etomidate, it can be deduced that the substances might differ in their anticonvulsant properties, resulting in a lower increase in stimulus intensity during the course of treatment under etomidate. Besides this hypothesis, we aimed to investigate the differential effects of etomidate and methohexital on clinical features, ECT parameters and side effects of the treatment. METHODS: We performed a retrospective analysis of treatment data of patients with affective and psychotic diagnosis who received general anesthesia for ECT either with etomidate or with methohexital. RESULTS: ECT with etomidate and methohexital was equally effective. During the course of therapies the administered electric charge increased significantly and equally in both treatment groups. In the methohexital group, but not in the etomidate group, electroencephalographic seizure duration had a declining trend during the course of therapies. We observed more side effects during and immediately after ECT in the methohexital group than in the etomidate group. LIMITATIONS: The limitations of this study are that the patients received various psychotropic co-medications, which influence ictal parameters differently, and, secondly, the study is based on a retrospective analysis. CONCLUSION: The results of our analysis suggest that etomidate and methohexital affect ictal parameters to different extents. Longer seizure duration and fewer side effects are in favor of etomidate.

The role of neurotrophic factors in autism.

Autism spectrum disorders (ASDs) are pervasive developmental disorders that frequently involve a triad of deficits in social skills, communication and language. For the underlying neurobiology of these symptoms, disturbances in neuronal development and synaptic plasticity have been discussed. The physiological development, regulation and survival of specific neuronal populations shaping neuronal plasticity require the so-called 'neurotrophic factors' (NTFs). These regulate cellular proliferation, migration, differentiation and integrity, which are also affected in ASD. Therefore, NTFs have gained increasing attention in ASD research. This review provides an overview and explores the key role of NTFs in the aetiology of ASD. We have also included evidence derived from neurochemical investigations, gene association studies and animal models. By focussing on the role of NTFs in ASD, we intend to further elucidate the puzzling aetiology of these conditions.

[Genetic and brain structure anomalies in autism spectrum disorders. Towards an understanding of the aetiopathogenesis?]. / Genetische und hirnstrukturelle Anomalien bei Autismus-Spektrum-Störungen. Eine Brücke zum Verständnis der Ätiopathogenese?

Autism spectrum disorders (ASD) are pervasive development disorders with high heritability and an as yet unclear aetiology. So far molecular genetic research was able to identify several candidate genes for the disorder which are functionally linked to neurotransmission and neuronal migration, cortical organisation and synaptic plasticity. MRI studies repeatedly showed a higher total brain volume for ASD patients. The volume increase was most pronounced for the frontal and the temporal lobes and peaked in early childhood. A combination of molecular genetic and structural imaging research appears promising for a further characterization of ASD aetiology.

[Meta-analyses in clinical brain research]. / Metaanalysen in der klinischen Hirnforschung.

Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have brought about an immense increase in findings on the localization of motor, cognitive, and affective processes in the human brain. However, considerable discrepancy still exists between the multitude of available studies and the limited validity of the individual experiments. Quantitative, coordinate-based meta-analyses are suited to objectively integrate these numerous findings as completely as possible. There are a number of different methods for coordinate-based voxel-wise meta-analyses, but the technique of"activation likelihood estimation" (ALE) has largely prevailed. This contribution describes the principles, methods, and statistical analysis of ALE meta-analyses and their potential for basic research in neuroscience and clinical brain research.

[Correlations between risk gene variants for schizophrenia and brain structure anomalies]. / Korrelation zwischen Risikogenvarianten für Schizophrenie und Hirnstrukturanomalien.

The specific etiologies of schizophrenia are largely unknown. Genetic predisposition constitutes an important, however, not exclusive risk factor for the development of schizophrenia. In recent years, a number of candidate genes were identified and have been consistently replicated. Magnetic resonance imaging studies have characterized structural changes in brain morphology, such as ventricular enlargement or volume reduction of the medial temporal structures and the superior temporal gyrus. Several studies have found correlations between gene variants and changes of brain morphology in schizophrenia patients and healthy controls. In this review, publications examining correlations of schizophrenia susceptibility gene polymorphisms and structural brain anomalies in patients and healthy controls are described. An overview and a critical reflection of the current research are outlined. The results of genome-wide studies will soon provide a multitude of additional schizophrenia susceptibility genes. If and to what extent these genes exert an influence on the brain structure in the healthy and the diseased, can be clarified by gene structure correlations. Given the many possible gene-gene and gene-environment interactions, most variants will probably not show simple interactions with sizable effects.

Psychiatric symptoms in a patient with Wolfram syndrome caused by a combination of thalamic deficit and endocrinological pathologies.

DIDMOAD or Wolfram syndrome is a hereditary disorder characterized by early onset diabetes and optic atrophy. Besides these features, a variety of other symptoms have been described including psychiatrical abnormalities leading to hospitalization in about 25% of all patients. To our knowledge, until now, a detailed characterization of these psychiatric symptoms does not exist. Here we describe a 21-year-old male patient with deficits of frontal lobe function, such as impaired impulse control and learning deficits. Magnetic resonance imaging (MRI) of the brain showed a bilateral optic atrophy, but no signs of frontal brain atrophy. Neuropsychological tests revealed performance deficits in complex planning (e.g., Tower of London). Also his capacities in memorizing logically connected information after a short and delayed period of time were significantly reduced. Since histopathological studies did not reveal frontal brain abnormalities, but did show thalamic neuronal loss and gliosis, we interpret our findings as representative of thalamic dysfunction. In addition, hypoglycaemia seemed to trigger rapid mood swings. As soon as blood glucose levels improved, the patient stabilized emotionally and assaultive behaviour disappeared while the cognitive deficits remained unchanged.

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-beta2.

Versican is a large chondroitin sulphate proteoglycan produced by several tumour cell types, including high-grade glioma. The increased expression of certain versican isoforms in the extracellular matrix (ECM) plays a role in tumour cell growth, adhesion and migration. Transforming growth factor-beta2 (TGF-beta2) is an important modulator of glioma invasion, partially by remodeling the ECM. However, it is unknown whether it interacts with versican during malignant progression of glioma cells. Here, we analysed the effect of TGF-beta2 on the expression of versican isoforms. The expression of versican V0/V1 was upregulated by TGF-beta2 detected by quantitative polymerase chain reaction and immunoprecipitation, whereas V2 was not induced. Using time-lapse scratch and spheroid migration assays, we observed that the glioma migration rate is significantly increased by exogenous TGF-beta2 and inhibited by TGF-beta2-specific antisense oligonucleotides. Interestingly, an antibody specific for the DPEAAE region of glycosaminoglycan-beta domain of versican was able to reverse the effect of TGF-beta2 on glioma migration in a dose-dependent manner. Taken together, we report here that TGF-beta2 triggers the malignant phenotype of high-grade gliomas by induction of migration, and that this effect is, at least in part, mediated by versican V0/V1.

An imbalance between Smad and MAPK pathways is responsible for TGF-beta tumor promoting effects in high-grade gliomas.

The transforming growth factor-beta (TGF-beta) plays a pivotal role in the pathobiology of human gliomas: during carcinogenesis, it turns from a tumor suppressor to a tumor promoter. The traditional Smad pathway and the more recently discovered MAPK pathway are the most important pathways for TGF-beta related intracellular signal transduction mediating differential pathobiological effects. In this study, we investigated the effects of TGF-beta2 and the TGF-beta2 antisense phosphorothioate oligodeoxynucleotide (PTO) AS-11 on the functionality of both the Smad and MAPK pathways in high-grade gliomas. We aimed to correlate the imbalance between the pathways with differences in the behaviour of high-grade glioma cells. Gene and protein expression studies were used to detect levels of members of the Smad and MAPK pathways under regulation of TGF-beta2 and AS-11. Proliferation and migration assays were functional readouts for effects caused by these regulating tools. Gene arrays were used to detect yet unknown regulators of these functional effects. The Smad pathway was functional in the tested cell lines. Exogenous TGF-beta2 inhibited proliferation but enhanced migration. Smad 2 mRNA expression and activation were significantly reduced by incubation with AS-11. K-ras was reduced both in gene arrays and quPCR under treatment with AS-11, but there was no influence of K-ras down-regulation on the activity of ERK. Ubiquitination-related genes also were specifically down-regulated with AS-11. Our results indicate the involvement of K-ras in TGF-beta signaling in high-grade gliomas. ERK, which is a member of the MAPK pathway, was not influenced and seems to be activated through RAS independent cascades in glioma. These results suggest that combined antagonization of the TGF-beta and MAPK pathways might be a promising approach for glioma therapy. An imbalance between these two pathways might be responsible for TGF-beta switching to a tumor promoter protein in high-grade gliomas.