The Role of the N-Methyl-D-Aspartate Receptors in Social Behavior in Rodents

The appropriate display of social behaviors is essential for the well-being, reproductive success and survival of an individual. Deficits in social behavior are associated with impaired N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. In this review, we describe recent studies using genetically modified mice and pharmacological approaches which link the impaired functioning of the NMDA receptors, especially of the receptor subunits GluN1, GluN2A and GluN2B, to abnormal social behavior. This abnormal social behavior is expressed as impaired social interaction and communication, deficits in social memory, deficits in sexual and maternal behavior, as well as abnormal or heightened aggression. We also describe the positive effects of pharmacological stimulation of the NMDA receptors on these social deficits. Indeed, pharmacological stimulation of the glycine-binding site either by direct stimulation or by elevating the synaptic glycine levels represents a promising strategy for the normalization of genetically-induced, pharmacologically-induced or innate deficits in social behavior. We emphasize on the importance of future studies investigating the role of subunit-selective NMDA receptor ligands on different types of social behavior to provide a better understanding of the underlying mechanisms, which might support the development of selective tools for the optimized treatment of disorders associated with social deficits

Diversitätsintelligenz

„Diversitätsintelligenz“ bezeichnet den kognitiven Vorteil einer Gruppe von Personen mit unterschiedlichen Eigenschaften; ihre kollektive intellektuelle Besonderheit basiert auf der offenbaren Überlegenheit komiteebasierter Mehrheiten, deren Entscheidungen sich aus vielen einzelnen Teilinformationen zusammensetzen, die sie ganz unterschiedlichen individuellen Erkenntnissen, Erfahrungen und Einsichten zu verdanken haben. Komiteebasierte Entscheidungen werden universell genutzt. Für das Wirken unseres Nervensystems sind sie ebenso verantwortlich, wie für das Funktionieren von Vogelschwärmen, von Demokratien oder der Algorithmen von Google und anderer Klassifikationsberechnungen. Mit Diversitätsintelligenz können, wie der folgende Beitrag* mit vielen Beispielen zeigt, sowohl Fragen der Gegenwart als auch Fragen an die Zukunft gut beantwortet werden. Es gibt jedoch auch Formen der Diversitätsintelligenz, die auf der Interaktion zwischen Individuen beruhen, vor allem in Büros, Verwaltungen und anderen menschlichen Gemeinschaften. Dazu gehören das Brainstorming, Consensus-Konferenzen oder multidisziplinäre Fallbesprechungen. Aber, so veranschaulicht der folgende Beitrag die Nutzung und Anwendung diversitätsintelligenter Optionen: bei der direkten Interaktion in der Gruppe muss sehr sorgfältig darauf geachtet werden, dass eine Atmosphäre der freien Meinungsäußerung und geistiger Raum für die Rezeption und Verarbeitung auch ungewohnter und fremdartiger Gedanken möglich sind

Sphingomyelin Synthases in Neuropsychiatric Health and Disease

Sphingomyelin synthases (SMS) catalyze the conversion of ceramide and phosphatidylcholine to sphingomyelin and diacylglycerol and are thus crucial for the balance between synthesis and degradation of these structural and bioactive molecules. SMS thereby play an essential role in sphingolipid metabolism, cell signaling, proliferation and differentiation processes. Although tremendous progress has been made toward understanding the involvement of SMS in physiological and pathological processes, literature in the area of neuropsychiatry is still limited. In this review, we summarize the main features of SMS as well as the current methodologies and tools used for their study and provide an overview of SMS in the central nervous system and their implications in neurological as well as psychiatric disorders. This way, we aim at establishing a basis for future mechanistic as well as clinical investigations on SMS in neuropsychiatric health and diseases

Gustav Nikolaus Specht (1860–1940) : Sein Einfluss auf die Nosologie Kraepelins und Annäherungen an seine Position im Nationalsozialismus

Hinführung Gustav Specht steht am Anfang der Erlanger Universitätspsychiatrie. 80 Jahre nach seinem Tod untersucht der vorliegende Artikel insbesondere die Rolle Spechts bei der von Kraepelin ausgehenden psychopathologisch-nosologischen Diskussion. Trotz spärlicher Datenlage unternehmen die Autoren erstmals eine Annäherung an Spechts Positionen innerhalb der nationalsozialistischen Psychiatrie. Methode Relevantes archivalisches Material sowie Primär- und Sekundärliteratur wurden ausgewertet. Ergebnisse Specht wurde 1897 zum außerplanmäßigen Professor und 1903 zum ersten Ordinarius für Psychiatrie in Erlangen ernannt. Specht arbeitete die Bedeutung des manischen Elementes in der Paranoia heraus. Specht ergänzte den sog. „exogenen Reaktionstypus“ Bonhoeffers 1913 um die depressiven Zustandsbilder; er selbst war – bei fremddiagnostischem Verdacht auf zyklothymes Temperament – zweimalig exogen reaktiv depressiv erkrankt. Diskussion Durch seine Forschungsarbeiten zum pathologischen Affekt in der chronischen Paranoia beeinflusste Specht die zeitgenössische psychopathologische Diskussion nachhaltig. Spechts Perspektivenwechsel in puncto „Erbgesundheit“ lässt sich interpretieren als Anpassung an das NS-Regime. Schlussfolgerung Das Werk Gustav Spechts kann u. a. dazu anregen, einen interdisziplinären psychopathologischen Diskurs zu kultivieren

Neuropeptide Y reduces expression of social fear via simultaneous activation of Y1 and Y2 receptors

Background: Neuropeptide Y (NPY) has anxiolytic effects and facilitates extinction of cued and contextual fear in rodents, thereby acting as a resilience factor against exaggerated fear responses after adverse events. We investigated whether NPY influences acquisition, expression and extinction of social fear in a mouse model of social fear conditioning (SFC). Methods: NPY was administered intracerebroventricularly before SFC or before social fear extinction with or without prior administration of Y1 and/or Y2 receptor antagonists. Results: We show that NPY affects SFC-induced social fear in a time point–dependent manner. When administered before SFC, NPY did not affect acquisition, expression and extinction of social fear. However, when administered before social fear extinction, NPY reduced expression of social fear via simultaneous activation of Y1 and Y2 receptors. As such, neither the Y1 receptor antagonist BIBO3304 trifluoroacetate nor the Y2 receptor antagonist BIIE0246 was able to block the effects of NPY completely. However, when administered in combination, they completely blocked the effects of NPY on social fear expression. Conclusions: These findings have important clinical implications, as they suggest that although medication strategies aimed at increasing brain NPY activity are unlikely to prevent the formation of aversive memories after a traumatic social experience, they might improve the recovery from a traumatic social experience by reducing the expression of social fear

Neuropeptide Y as Alternative Pharmacotherapy for Antidepressant-Resistant Social Fear

In many social anxiety disorder (SAD) patients, the efficacy of antidepressant therapy is unsatisfactory. Here, we investigated whether mice deficient for the lysosomal glycoprotein acid sphingomyelinase (ASM−/−) represent an appropriate tool to study antidepressant-resistant social fear. We also investigated whether neuropeptide Y (NPY) reduces this antidepressant-resistant social fear in ASM−/− mice, given that NPY reduced social fear in a mouse model of SAD, namely social fear conditioning (SFC). We show that neither chronic paroxetine nor chronic amitriptyline administration via drinking water were successful in reducing SFC-induced social fear in ASM−/− mice, while the same treatment reduced social fear in ASM+/− mice and completely reversed social fear in ASM+/+ mice. This indicates that the antidepressants paroxetine and amitriptyline reduce social fear via the ASM-ceramide system and that ASM−/− mice represent an appropriate tool to study antidepressant-resistant social fear. The intracerebroventricular administration of NPY, on the other hand, reduced social fear in ASM−/− mice, suggesting that NPY might represent an alternative pharmacotherapy for antidepressant-resistant social fear. These results suggest that medication strategies aimed at increasing brain NPY concentrations might improve symptoms of social fear in SAD patients who fail to respond to antidepressant treatments

Brain Region-Dependent Effects of Neuropeptide Y on Conditioned Social Fear and Anxiety-Like Behavior in Male Mice

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We have previously shown that the intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC). In the present study, we aimed to identify the brain regions that mediate these effects of NPY. We show that NPY (0.1 nmol/0.2 µL/side) reduces the expression of SFC-induced social fear in a brain-region-dependent manner. In more detail, NPY reduced the expression of social fear when administered into the dorsolateral septum (DLS) and central amygdala (CeA), but not when administered into the dorsal hippocampus (DH), medial amygdala (MeA) and basolateral amygdala (BLA). We also investigated whether the reduced expression of social fear might partly be due to a reduced anxiety-like behavior, and showed that NPY exerted anxiolytic-like effects when administered into the DH, DLS, CeA and BLA, but not when administered into the MeA. This study identifies the DLS and the CeA as brain regions mediating the effects of NPY on the expression of social fear and suggests that partly distinct neural circuitries mediate the effects of NPY on the expression of social fear and on anxiety-like behavior

New Molecular Targets for Antidepressant Drugs

Major depressive disorder (MDD) is a common and severe mental disorder that is usually recurrent and has a high risk of suicide. This disorder manifests not only with psychological symptoms but also multiple changes throughout the body, including increased risks of obesity, diabetes, and cardiovascular disease. Peripheral markers of oxidative stress and inflammation are elevated. MDD is therefore best described as a multisystem whole-body disease. Pharmacological treatment with antidepressants usually requires several weeks before the desired effects manifest. Previous theories of depression, such as the monoamine or neurogenesis hypotheses, do not explain these characteristics well. In recent years, new mechanisms of action have been discovered for long-standing antidepressants that also shed new light on depression, including the sphingolipid system and the receptor for brain-derived neurotrophic factor (BDNF)

Cerebrospinal Fluid Tau, p-Tau 181 and Amyloid-beta(38/40/42) in Frontotemporal Dementias and Primary Progressive Aphasias

Background/Aims: We determined cerebrospinal fluid (CSF) concentrations of amyloid-beta(A beta)(1-38), A beta(1-40), A beta(1-42), total tau and phospho-tau (p-tau) in order to study their differential expression in frontotemporal dementia (FTD, n = 25) and primary progressive aphasia (PPA, n = 12) as compared to Alzheimer's dementia (AD, n = 25) and nondemented controls (n = 20). Methods: Commercially available ELISA and electrochemiluminescence methods were applied. Results: High CSF p-tau and low ratios of A beta(1-42)/A beta(1-40) and A beta(1-42)/A beta(1-38), respectively, were specific for AD. CSF A beta(1-38) was reduced in FTD as compared to each of the other diagnostic groups, including PPA. CSF tau and p-tau levels were elevated in PPA as compared to FTD. Conclusion: This is the first detailed report on biomarker patterns in PPA, indicating distinct CSF biomarker patterns in FTD and PPA as major subgroups of frontotemporal lobar degeneration. The diagnostic and pathophysiological implications of our results warrant further studies on larger and neuropathologically diagnosed patient populations. Copyright (C) 2010 S. Karger AG, Base

Development of Comorbid Depression after Social Fear Conditioning in Mice and Its Effects on Brain Sphingolipid Metabolism

Currently, there are no animal models for studying both specific social fear and social fear with comorbidities. Here, we investigated whether social fear conditioning (SFC), an animal model with face, predictive and construct validity for social anxiety disorder (SAD), leads to the development of comorbidities at a later stage over the course of the disease and how this affects the brain sphingolipid metabolism. SFC altered both the emotional behavior and the brain sphingolipid metabolism in a time-point-dependent manner. While social fear was not accompanied by changes in non-social anxiety-like and depressive-like behavior for at least two to three weeks, a comorbid depressive-like behavior developed five weeks after SFC. These different pathologies were accompanied by different alterations in the brain sphingolipid metabolism. Specific social fear was accompanied by increased activity of ceramidases in the ventral hippocampus and ventral mesencephalon and by small changes in sphingolipid levels in the dorsal hippocampus. Social fear with comorbid depression, however, altered the activity of sphingomyelinases and ceramidases as well as the sphingolipid levels and sphingolipid ratios in most of the investigated brain regions. This suggests that changes in the brain sphingolipid metabolism might be related to the short- and long-term pathophysiology of SAD