Refine
Has Fulltext
- yes (2)
Is part of the Bibliography
- yes (2)
Year of publication
- 2018 (2) (remove)
Document Type
- Doctoral Thesis (2)
Keywords
- Knockout (2) (remove)
Anxiety and depressive disorders result from a complex interplay of genetic and environmental factors and are common mutual comorbidities. On the level of cellular signaling, regulator of G protein signaling 2 (Rgs2) has been implicated in human and rodent anxiety as well as rodent depression. Rgs2 negatively regulates G protein-coupled receptor (GPCR) signaling by acting as a GTPase accelerating protein towards the Gα subunit.
The present study investigates, whether mice with a homozygous Rgs2 deletion (Rgs2-/-) show behavioral alterations as well as an increased susceptibility to stressful life events related to human anxiety and depressive disorders and tries to elucidate molecular underlying’s of these changes.
To this end, Rgs2-/- mice were characterized in an aversive-associative learning paradigm to evaluate learned fear as a model for the etiology of human anxiety disorders. Spatial learning and reward motivated spatial learning were evaluated to control for learning in non-aversive paradigms. Rgs2 deletion enhanced learning in all three paradigms, rendering increased learning upon deletion of Rgs2 not specific for aversive learning. These data support reports indicating increased long-term potentiation in Rgs2-/- mice and may predict treatment response to conditioning based behavior therapy in patients with polymorphisms associated with reduced RGS2 expression. Previous reports of increased innate anxiety were corroborated in three tests based on the approach-avoidance conflict. Interestingly, Rgs2-/- mice showed novelty-induced hypo-locomotion suggesting neophobia, which may translate to the clinical picture of agoraphobia in humans and reduced RGS2 expression in humans was associated with a higher incidence of panic disorder with agoraphobia. Depression-like behavior was more distinctive in female Rgs2-/- mice. Stress resilience, tested in an acute and a chronic stress paradigm, was also more distinctive in female Rgs2-/- mice, suggesting Rgs2 to contribute to sex specific effects of anxiety disorders and depression.
Rgs2 deletion was associated with GPCR expression changes of the adrenergic, serotonergic, dopaminergic and neuropeptide Y systems in the brain and heart as well as reduced monoaminergic neurotransmitter levels. Furthermore, the expression of two stress-related microRNAs was increased upon Rgs2 deletion. The aversive-associative learning paradigm induced a dynamic Rgs2 expression change. The observed molecular changes may contribute to the anxious and depressed phenotype as well as promote altered stress reactivity, while reflecting an alter basal stress level and a disrupted sympathetic tone. Dynamic Rgs2 expression may mediate changes in GPCR signaling duration during memory formation.
Taken together, Rgs2 deletion promotes increased anxiety-like and depression-like behavior, altered stress reactivity as well as increased cognitive function.
Neuste Studien haben ergeben, dass Asc-1 Knock-out Mäuse aufgrund einer verminderten intrazellulären Glycinkonzentration in synaptischen Boutons im Gehirn, einen Hyperekplexie-ähnlichen Phänotyp entwickeln. Aufgrund nicht vollständig geklärter Ursachen für die Entstehung des Krankheitsbildes der Hyperekplexie beim Menschen, wurde eine Kohorte von 51 Patienten zusammengetragen, um vor dem Hintergrund der Forschungsergebnisse zu Asc-1 im Tiermodell, das kodierende Gen beim Menschen SLC7A10 als mögliches Kandidatengen auf Sequenzalterationen zu untersuchen. Hierfür wurde aus Vollblut der an Hyperekplexie erkrankten Patienten genomische DNA isoliert, um mittels PCR und anschließendem Screening der Sequenzen, Mutationen innerhalb funktionell wichtiger Bereiche des Gens zu eruieren. Neben weiteren Sequenzunterschieden, die meist in Introns gefunden wurden, wurde die codierende Mutation G307R innerhalb von Exon 7 identifiziert, die letztendlich der Grund für eine Versuchsreihe war, um zu hinterfragen, ob dieser Aminosäureaustausch in der Proteinsequenz funktionelle Konsequenzen zur Folge hat. HEK293-Zellen wurden mit dem zuvor hergestellten Klon G307R transfiziert, um über Biotinylierung, immuncytochemische Färbungen und funktionelle Untersuchungen die Aktivität des Transporters zu beurteilen. Hier zeigte sich ein Funktionsverlust von über 95 %, bei uneingeschränkter Oberflächenexpression. ASC-1 bestätigt sich damit als neue Ursache in der Ausprägung von Hyperekplexie. Ferner können Zusammenhänge mit geistiger Retardierung und eingeschränkter neuronaler Plastizität bestehen.