The ionotropic P2X7-receptor residing in the plasma membrane belongs to the P2X-family of ligand-gated ion channels. It consists of 13 exons encoding a protein of 595 aminoacids. The receptor forms ...homomeric complexes that open large channels when activated by extracellular ATP. In some cell types, these channels are permeable to molecules up to 900 Da, whereas in others they are permeable only to smaller molecules or exhibit ion selectivity. Although the main function known so far is to mediate several responses in inflammation through processing Il1ß, the receptor is as well involved in neurotransmission, modulating glutamate and GABA release. P2X7 receptors in the nervous system have been localized to microglia, neuronal processes, Müller cells, Schwann cells and astrocytes. In presynaptic terminals it is colocalised with vesicular glutamate transporters. P2X7 was identified as a candidate for depression with the help of linkage studies in different populations (Canada, Germany, United Kingdom). The data are validated through SNP based genotyping in patients and search for SNPs in the MARS-database. The aim of the project is to create and characterize mice in which the mouse sequence was 1. knocked out, 2. replaced through human wt-Sequence, and 3. substituted by a human sequences in which the most prominent SNP is inserted. These mice should be valuable tools to test the efficiency of P2X7-specific drugs and to dissect molecular pathways downstream of P2X7 potentially involved in depression.
Corticotropin-releasing hormone (CRH) plays a key role in coordinating the responses to a variety of stress-associated stimuli. Recent clinical data implicate CRH in the pathophysiology of human ...affective disorders. To dissect CRH/
Crhr1
central nervous system pathways modulating behaviour from those regulating neuroendocrine function, we generated a conditional knockout mouse line (
Crhr1
loxP/loxP
CaMKIIαCre
) in which Crhr1 function is inactivated postnatally in anterior forebrain and limbic brain structures while sparing pituitary expression sites, so as to leave hypothalamic-pituitary-adrenocortical (HPA) system regulation intact.
Crhr1
loxP/loxP
CaMKIIαCre
mutants display reduced anxiety while basal activity of the HPA system is normal. In contrast to
Crhr1
null mutants, conditional mutants are hypersensitive to stress: ACTH and corticosterone levels remain significantly elevated post-stress. Our data clearly show that limbic
Crhr1
is modulating anxiety-related behaviour, and that this effect is independent of HPA system function. Furthermore, we provide evidence for a novel role of limbic
Crhr1
in neuroendocrine adaptation to stress.
Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the ...absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.
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