Personality systems interactions theory: an integrative framework complementing the study of the motivational and volitional dynamics underlying adjustment to chronic pain.

In the endeavor to advance our understanding of interindividual differences in dealing with chronic pain, numerous motivational theories have been invoked in the past decade. As they focus on relevant, yet different aspects of the dynamic, multilevel processes involved in human voluntary action control, research findings seem fragmented and inconsistent. Here we present Personality Systems Interactions theory as an integrative meta-framework elucidating how different motivational and volitional processes work in concert under varying contextual conditions. PSI theory explains experience and behavior by the relative activation of four cognitive systems that take over different psychological functions during goal pursuit. In this way, it may complement existing content-related explanations of clinical phenomena by introducing a functional, third-person perspective on flexible goal management, pain acceptance and goal maintenance despite pain. In line with emerging evidence on the central role of emotion regulation in chronic pain, PSI theory delineates how the self-regulation of positive and negative affect impacts whether behavior is determined by rigid stimulus-response associations (i.e., habits) or by more abstract motives and values which afford more behavioral flexibility. Along with testable hypotheses, multimodal interventions expected to address intuitive emotion regulation as a central process mediating successful adaptation to chronic pain are discussed.

[Dealing with "complex" pain patients in eye surgery : Perioperative management of patients with pre-existing chronic pain, opioid consumption and opioid use disorder]. / Umgang mit "komplexen" Schmerzpatienten bei Augeneingriffen : Perioperatives Management von Patienten mit vorbestehenden chronischen Schmerzen, Opioidvormedikation und Opioidabhängigkeit.

The quality of postoperative pain management is still considered insufficient in many cases, also in surgical ophthalmology. Complex constellations and comorbidities, such as pre-existing chronic pain, opioid consumption and opioid use disorders represent a special challenge due to psychosocial influencing factors and sometimes psychological and psychiatric comorbidities but also due to pharmacological effects, such as the development of opioid tolerance, the opioid-induced hyperalgesia. This review article aims to impart knowledge on aspects of these comorbidities and the perioperative management to improve the treatment skills of ophthalmologists in the management of pain in these complex patients.

Pain chronification impacts whole-brain functional connectivity in women with hip osteoarthritis during pain stimulation.

OBJECTIVE: Previous neuroimaging studies have shown that patients with chronic pain display altered functional connectivity across distributed brain areas involved in the processing of nociceptive stimuli. The aim of the present study was to investigate how pain chronification modulates whole-brain functional connectivity during evoked clinical and tonic pain. METHODS: Patients with osteoarthritis of the hip (n = 87) were classified into 3 stages of pain chronification (Grades I-III, Mainz Pain Staging System). Electroencephalograms were recorded during 3 conditions: baseline, evoked clinical hip pain, and tonic cold pain (cold pressor test). The effects of both factors (recording condition and pain chronification stage) on the phase-lag index, as a measure of neuronal connectivity, were examined for different frequency bands. RESULTS: In women, we found increasing functional connectivity in the low-frequency range (delta, 0.5-4 Hz) across pain chronification stages during evoked clinical hip pain and tonic cold pain stimulation. In men, elevated functional connectivity in the delta frequency range was observed in only the tonic cold pain condition. CONCLUSIONS: Across pain chronification stages, we found that widespread cortical networks increase their synchronization of delta oscillations in response to clinical and experimental nociceptive stimuli. In view of previous studies relating delta oscillations to salience detection and other basic motivational processes, our results hint at these mechanisms playing an important role in pain chronification, mainly in women.

Evidence for PKD2L1-positive neurons distant from the central canal in the ventromedial spinal cord and medulla of the adult mouse.

Neurons in contact with the cerebrospinal fluid (CSF) are found around the medullo-spinal central canal (CC) in adult mice. These neurons (CSF-cNs), located within or below the ependymal cell layer, known as the stem cell niche, present a characteristic morphology with a dendrite projecting to the CC and ending with a protrusion. They are GABAergic, present an intermediate neuronal maturity and selectively express PKD2L1, a member of the transient receptor potential channel superfamily with sensory properties. Using immunohistological and electrophysiological recording techniques in mice, we characterize the properties of a new population of PKD2L1 positive cells that is distant from the CC in a zone enriched with astrocytes and ependymal fibers of the ventro-medial spinal cord and medulla. They appear around embryonic day 16 and their number increases up to early postnatal days. With development and the reorganization of the CC region, they progressively become more distant from the CC, suggesting some migratory capabilities. These neurons share functional and phenotypical properties with CSF-cNs but appear subdivided in two groups. One group, present along the midline, has a bipolar morphology and extends a long dendrite along ependymal fibers and towards the CC. The second group, localized in more ventro-lateral regions, has a multipolar morphology and no apparent projection to the CC. Altogether, we describe a novel population of PKD2L1+ neurons distant from the CC but with properties similar to CSF-cNs that might serve to sense modification in the composition of either CSF or interstitial liquid, a function that will need to be confirmed.

The virtue of optimistic realism - expectation fulfillment predicts patient-rated global effectiveness of total hip arthroplasty.

BACKGROUND: Emerging evidence highlights the importance of preoperative expectations in predicting patient-reported outcomes of orthopedic surgeries. To date, it is still a matter of controversy whether patient satisfaction can be maximized by promoting either optimistic or realistic outcome expectations before surgery. Adjusting overly optimistic outcome expectancies in favor of a more realistic outlook on the limitations of total hip arthroplasty could reduce the risk of disappointment and lead to greater satisfaction with surgery outcomes. Our prospective cohort study was aimed at comparing the relative predictive influence of baseline expectations, expectation fulfillment and symptomatic improvement on the global effectiveness of total hip arthroplasty. METHODS: Ninety patients (49 female, 41 male; mean age: 63 ± 12.87 years) fulfilled inclusion criteria and completed a comprehensive preoperative assessment comprising sociodemographic, clinical, functional and psychological phenotypes. Moreover, the strengths of preoperative expectations for improvements in eight pain-related and functional domains were recorded on a 5-point Likert-scale. At 12 months after surgery, patients were asked to rate perceived improvements in each of these domains as well as the global effectiveness of the total hip replacement on a 5-point Likert-scale. To evaluate the relative impact of preoperative expectations, symptom improvement and the fulfillment of expectations on the global effectiveness of surgery, a sequential multiple regression analysis was performed. RESULTS: Compared with the actual improvement at 12-months follow-up, prior expectations had been overly optimistic in about 28% of patients for hip pain, in about 45% for walking ability and around 60% for back pain, independence in everyday life, physical exercise, general function social interactions and mental well-being. An optimistic hip pain expectation, walking ability at baseline and the fulfillment of expectations for walking ability, general function and independence in everyday life were found to independently predict global effectiveness ratings. CONCLUSIONS: Positive expectation about pain and the fulfillment of expectations concerning functional domains predicted higher global effectiveness ratings. In line with many authors investigating the relationship between the fulfillment of expectations and satisfaction with medical interventions, we suggest that professionals should explicitly address their patients' expectations during the preoperative education and consultation.

The influence of pain expectation on pain experience after orthopedic surgery: an observational cohort study.

BACKGROUND: Current literature about the effects of patients' expectations on relevant outcome measures is still conflicting and incomplete. The aim of this prospective observational study was to assess the influence of expectations and the fulfillment of expectations on postoperative pain intensity and pain relief. Furthermore, clinical characteristics influencing expectations and the fulfillment of expectations were explored. METHODS: Patients undergoing elective orthopedic surgery were assessed using two standardized self-report questionnaires on the day before surgery and the third postoperative day. One hundred and seventy patients from 21 to 93 years (average age 64.6, SD 14.0 years; 55% female) were consecutively included. RESULTS: While expectations of pain intensity did not correlate with pain experience after surgery, the fulfillment of expectations was associated with postoperative pain experience. Patients whose expectations were fulfilled were found to be more satisfied with the overall treatment as compared to those whose expectations were not fulfilled. Higher levels of expected pain were associated with higher fear of surgery and fear of postoperative pain. Preoperative pain intensity, length of treatment before the surgery, fear of surgery, helplessness and fear of postoperative pain were associated with higher postoperative pain intensity. Lower levels of preoperative fear of surgery and fear of postoperative pain were found to correlate with the fulfillment of pain relief. CONCLUSIONS: Our study indicates that postoperative pain and satisfaction with the treatment are associated with the degree of fulfillment of expectations rather than the expected pain itself.

Sustained cell body reactivity and loss of NeuN in a subset of axotomized bulbospinal neurons after a chronic high cervical spinal cord injury.

Following central nervous system lesion, the ability of injured axons to regrowth may depend on the level and duration of the injured cell body response (CBR). Therefore, to investigate whether axotomized brainstem neurons maintain a durable growth-competent state after spinal cord injury, we studied the effect of a chronic C2 hemisection in rats on the expression of various CBR markers involved in axon regeneration, such as c-Jun, ATF-3, HSP27, NO synthase (NOS), and also of the neural mature phenotype marker NeuN, in the bulbospinal respiratory neurons as compared to the gigantocellularis nucleus. Both at 7 and 30 days post-lesion (DPL), c-Jun and HSP27 were present in, respectively, ~60 and ~20% of the axotomized respiratory neurons, whereas the apoptotic factor caspase 3 was not detected in these cells. NOS appeared belatedly, and it was detected in ~20% of the axotomized respiratory neurons at 30DPL. At 30DPL, these different CBR markers were strongly colocalized in a sub-population of axotomized respiratory neurons and also in a sub-population of injured neurons within the gigantocellularis nucleus. Such CBR was also accompanied by a sustained alteration of the neural mature phenotype, as indicated by a loss of NeuN immunoreactivity selectively in HSP27+ bulbospinal neurons at 7DPL and 30DPL. Altogether, this study shows that a subset of axotomized medullary respiratory neurons remains in a growth-competent state after a chronic injury, suggesting that they may play a preferential role in long-lasting respiratory neuroplasticity processes.

Microbial communities in carbonate rocks-from soil via groundwater to rocks.

Microbial communities in soil, groundwater, and rock of two sites in limestone were investigated to determine community parameters differentiating habitats in two lithostratigraphic untis. Lower Muschelkalk and Middle Muschelkalk associated soils, groundwater, and rock samples showed different, but overlapping microbial communities linked to carbon fluxes. The microbial diversities in soil were highest, groundwater revealed overlapping taxa but lower diversity, and rock samples were predominantly characterized by endospore forming bacteria and few archaea. Physiological profiles could establish a differentiation between habitats (soil, groundwater, rock). From community analyses and physiological profiles, different element cycles in limestone could be identified for the three habitats. While in soil, nitrogen cycling was identified as specific determinant, in rock methanogenesis linked carbonate rock to atmospheric methane cycles. These patterns specifically allowed for delineation of lithostratigraphic connections to physiological parameters.

Postnatal maturation of mouse medullo-spinal cerebrospinal fluid-contacting neurons.

The central canal along the spinal cord (SC.) and medulla is characterized by the presence of a specific population of neurons that contacts the cerebrospinal fluid (CSF). These medullo-spinal CSF-contacting neurons (CSF-cNs) are identified by the selective expression of the polycystin kidney disease 2-like 1 ionic channel (PKD2L1 or polycystin-L). In adult, they have been shown to express doublecortin (DCX) and Nkx6.1, two markers of juvenile neurons along with the neuron-specific nuclear protein (NeuN) typically expressed in mature neurons. They were therefore suggested to remain in a rather incomplete maturation state. The aim of this study was to assess whether such juvenile state is stable in postnatal animals or whether CSF-cNs may reach maturity at older stages than neurons in the parenchyma. We show, in the cervical SC. and the brainstem that, in relation to age, CSF-cN density declines and that their cell bodies become more distant from the cc, except in its ventral part. Moreover, in adults (from 1month) by comparison with neonatal mice, we show that CSF-cNs have evolved to a more mature state, as indicated by the increase in the percentage of cells positive for NeuN and of its level of expression. In parallel, CSF-cNs exhibit, in adult, lower DCX immunoreactivity and do not express PSA-NCAM and TUC4, two neurogenic markers. Nevertheless, CSF-cNs still share in adult characteristics of juvenile neurons such as the presence of phospho-CREB and DCX while NeuN expression remained low. This phenotype persists in 12-month-old animals. Thus, despite a pursuit of neuronal maturation during the postnatal period, CSF-cNs retain a durable low differentiated state.

Neuroprotective and Neurorestorative Processes after Spinal Cord Injury: The Case of the Bulbospinal Respiratory Neurons.

High cervical spinal cord injuries interrupt the bulbospinal respiratory pathways projecting to the cervical phrenic motoneurons resulting in important respiratory defects. In the case of a lateralized injury that maintains the respiratory drive on the opposite side, a partial recovery of the ipsilateral respiratory function occurs spontaneously over time, as observed in animal models. The rodent respiratory system is therefore a relevant model to investigate the neuroplastic and neuroprotective mechanisms that will trigger such phrenic motoneurons reactivation by supraspinal pathways. Since part of this recovery is dependent on the damaged side of the spinal cord, the present review highlights our current understanding of the anatomical neuroplasticity processes that are developed by the surviving damaged bulbospinal neurons, notably axonal sprouting and rerouting. Such anatomical neuroplasticity relies also on coordinated molecular mechanisms at the level of the axotomized bulbospinal neurons that will promote both neuroprotection and axon growth.

The brain as immunoprecipitator of serum autoantibodies against N-Methyl-D-aspartate receptor subunit NR1.

Autoantibodies (AB) against N-methyl-D-aspartate receptor subunit NR1 (NMDAR1) are highly seroprevalent in health and disease. Symptomatic relevance may arise upon compromised blood-brain barrier (BBB). However, it remained unknown whether circulating NMDAR1 AB appear in the cerebrospinal fluid (CSF). Of n = 271 subjects with CSF-serum pairs, 26 were NMDAR1 AB seropositive, but only 1 was CSF positive. Contrariwise, tetanus AB (non-brain-binding) were present in serum and CSF of all subjects, with CSF levels higher upon BBB dysfunction. Translational mouse experiments proved the hypothesis that the brain acts as an 'immunoprecipitator'; simultaneous injection of NMDAR1 AB and the non-brain-binding green fluorescent protein AB resulted in high detectability of the former in brain and the latter in CSF.

Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes.

Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high- versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.

Autism beyond diagnostic categories: characterization of autistic phenotypes in schizophrenia.

BACKGROUND: Behavioral phenotypical continua from health to disease suggest common underlying mechanisms with quantitative rather than qualitative differences. Until recently, autism spectrum disorders and schizophrenia were considered distinct nosologic entities. However, emerging evidence contributes to the blurring of symptomatic and genetic boundaries between these conditions. The present study aimed at quantifying behavioral phenotypes shared by autism spectrum disorders and schizophrenia to prepare the ground for biological pathway analyses. METHODS: Specific items of the Positive and Negative Syndrome Scale were employed and summed up to form a dimensional autism severity score (PAUSS). The score was created in a schizophrenia sample (N = 1156) and validated in adult high-functioning autism spectrum disorder (ASD) patients (N = 165). To this end, the Autism Diagnostic Observation Schedule (ADOS), the Autism (AQ) and Empathy Quotient (EQ) self-rating questionnaires were applied back to back with the newly developed PAUSS. RESULTS: PAUSS differentiated between ASD, schizophrenia and a disease-control sample and substantially correlated with the Autism Diagnostic Observation Schedule. Patients with ADOS scores ≥12 obtained highest, those with scores <7 lowest PAUSS values. AQ and EQ were not found to vary dependent on ADOS diagnosis. ROC curves for ADOS and PAUSS resulted in AuC values of 0.9 and 0.8, whereas AQ and EQ performed at chance level in the prediction of ASD. CONCLUSIONS: This work underscores the convergence of schizophrenia negative symptoms and autistic phenotypes. PAUSS evolved as a measure capturing the continuous nature of autistic behaviors. The definition of extreme-groups based on the dimensional PAUSS may permit future investigations of genetic constellations modulating autistic phenotypes.

Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender.

Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1 (+/-) females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1 (+/-) mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1 (+/-) females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

Mild expression differences of MECP2 influencing aggressive social behavior.

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3'UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3'UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.

Morphology, distribution and phenotype of polycystin kidney disease 2-like 1-positive cerebrospinal fluid contacting neurons in the brainstem of adult mice.

The mammalian spinal cord and medulla oblongata harbor unique neurons that remain in contact with the cerebrospinal fluid (CSF-cNs). These neurons were shown recently to express a polycystin member of the TRP channels family (PKD2L1) that potentially acts as a chemo- or mechanoreceptor. Recent studies carried out in young rodents indicate that spinal CSF-cNs express immature neuronal markers that appear to persist even in adult cells. Nevertheless, little is known about the phenotype and morphological properties of medullar CSF-cNs. Using immunohistochemistry and confocal microscopy techniques on tissues obtained from three-month old PKD2L1:EGFP transgenic mice, we analyzed the morphology, distribution, localization and phenotype of PKD2L1(+) CSF-cNs around the brainstem and cervical spinal cord central canal. We show that PKD2L1(+) CSF-cNs are GABAergic neurons with a subependymal localization, projecting a dendrite towards the central canal and an axon-like process running through the parenchyma. These neurons display a primary cilium on the soma and the dendritic process appears to bear ciliary-like structures in contact with the CSF. PKD2L1(+) CSF-cNs present a conserved morphology along the length of the medullospinal central canal with a change in their density, localization and dendritic length according to the rostro-caudal axis. At adult stages, PKD2L1(+) medullar CSF-cNs appear to remain in an intermediate state of maturation since they still exhibit characteristics of neuronal immaturity (DCX positive, neurofilament 160 kDa negative) along with the expression of a marker representative of neuronal maturation (NeuN). In addition, PKD2L1(+) CSF-cNs express Nkx6.1, a homeodomain protein that enables the differentiation of ventral progenitors into somatic motoneurons and interneurons. The present study provides valuable information on the cellular properties of this peculiar neuronal population that will be crucial for understanding the physiological role of CSF-cNs in mammals and their link with the stem cells contained in the region surrounding the medullospinal central canal.

Odor naming and interpretation performance in 881 schizophrenia subjects: association with clinical parameters.

BACKGROUND: Olfactory function tests are sensitive tools for assessing sensory-cognitive processing in schizophrenia. However, associations of central olfactory measures with clinical outcome parameters have not been simultaneously studied in large samples of schizophrenia patients. METHODS: In the framework of the comprehensive phenotyping of the GRAS (Göttingen Research Association for Schizophrenia) cohort, we modified and extended existing odor naming (active memory retrieval) and interpretation (attribute assignment) tasks to evaluate them in 881 schizophrenia patients and 102 healthy controls matched for age, gender and smoking behavior. Associations with emotional processing, neuropsychological test performance and disease outcome were studied. RESULTS: Schizophrenia patients underperformed controls in both olfactory tasks. Odor naming deficits were primarily associated with compromised cognition, interpretation deficits with positive symptom severity and general alertness. Contrasting schizophrenia extreme performers of odor interpretation (best versus worst percentile; N=88 each) and healthy individuals (N=102) underscores the obvious relationship between impaired odor interpretation and psychopathology, cognitive dysfunctioning, and emotional processing (all p<0.004). CONCLUSIONS: The strong association of performance in higher olfactory measures, odor naming and interpretation, with lead symptoms of schizophrenia and determinants of disease severity highlights their clinical and scientific significance. Based on the results obtained here in an exploratory fashion in a large patient sample, the development of an easy-to-use clinical test with improved psychometric properties may be encouraged.

Monogenic heritable autism gene neuroligin impacts Drosophila social behaviour.

Autism spectrum disorders (ASDs) are characterized by deficits in social interactions, language development and repetitive behaviours. Multiple genes involved in the formation, specification and maintenance of synapses have been identified as risk factors for ASDs development. Among these are the neuroligin genes which code for postsynaptic cell adhesion molecules that induce the formation of presynapses, promote their maturation and modulate synaptic functions in both vertebrates and invertebrates. Neuroligin-deficient mice display abnormal social and vocal behaviours that resemble ASDs symptoms. Here we show for the fly Drosophila melanogaster that deletion of the dnl2 gene, coding for one of four Neuroligin isoforms, impairs social interactions, alters acoustic communication signals, and affects the transition between different behaviours. dnl2-Deficient flies maintain larger distances to conspecifics and males perform less female-directed courtship and male-directed aggressive behaviours while the patterns of these behaviours and general locomotor activity were not different from wild type controls. Since tests for olfactory, visual and auditory perception revealed no sensory impairments of dnl2-deficient mutants, reduced social interactions seem to result from altered excitability in central nervous neuropils that initiate social behaviours. Our results demonstrate that Neuroligins are phylogenetically conserved not only regarding their structure and direct function at the synapse but also concerning a shared implication in the regulation of social behaviours that dates back to common ancestors of humans and flies. In addition to previously described mouse models, Drosophila can thus be used to study the contribution of Neuroligins to synaptic function, social interactions and their implication in ASDs.

Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism.

Autism is the short name of a complex and heterogeneous group of disorders (autism spectrum disorders, ASD) with several lead symptoms required for classification, including compromised social interaction, reduced verbal communication and stereotyped repetitive behaviors/restricted interests. The etiology of ASD is still unknown in most cases but monogenic heritable forms exist that have provided insights into ASD pathogenesis and have led to the notion of autism as a 'synapse disorder'. Among the most frequent monogenic causes of autism are loss-of-function mutations of the NLGN4X gene which encodes the synaptic cell adhesion protein neuroligin-4X (NLGN4X). We previously described autism-like behaviors in male Nlgn4 null mutant mice, including reduced social interaction and ultrasonic communication. Here, we extend the phenotypical characterization of Nlgn4 null mutant mice to both genders and add a series of additional autism-relevant behavioral readouts. We now report similar social interaction and ultrasonic communication deficits in females as in males. Furthermore, aggression, nest-building parameters, as well as self-grooming and circling as indicators of repetitive behaviors/stereotypies were explored in both genders. The construction of a gender-specific autism severity composite score for Nlgn4 mutant mice markedly diminishes population/sample heterogeneity typically obtained for single tests, resulting in p values of <0.00001 and a genotype predictability of 100% for male and of >83% for female mice. Taken together, these data underscore the similarity of phenotypical consequences of Nlgn4/NLGN4X loss-of-function in mouse and man, and emphasize the high relevance of Nlgn4 null mutant mice as an ASD model with both construct and face validity.

Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia.

Erythropoietin (EPO) improves cognitive performance in clinical studies and rodent experiments. We hypothesized that an intrinsic role of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations of EPO and EPO receptor (EPOR) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short-term memory readouts, with one particular combination of genotypes superior to all others (p < 0.0001). In an independent healthy control sample (N > 800), these associations were confirmed. A matching preclinical study with mice demonstrated cognitive processing speed and memory enhanced upon transgenic expression of constitutively active EPOR in pyramidal neurons of cortex and hippocampus. We thus predicted that the human genotypes associated with better cognition would reflect gain-of-function effects. Indeed, reporter gene assays and quantitative transcriptional analysis of peripheral blood mononuclear cells showed genotype-dependent EPO/EPOR expression differences. Together, these findings reveal a role of endogenous EPO/EPOR for cognition, at least in schizophrenic patients.