Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions

Abstract

The adrenomedullin (AM) gene, adm, is widely expressed in the central nervous system (CNS) and several functions have been suggested for brain AM. Until now, a formal confirmation of these actions using genetic models has been elusive since the systemic adm knockout results in embryo lethality. We have built a conditional knockout mouse model using the Cre/loxP approach. When crossed with transgenic mice expressing the Cre recombinase under the tubulin T␣-1 promoter, we obtained animals with no AM expression in the CNS but normal levels in other organs. These animals lead normal lives and do not present any gross morphological defect. Specific areas of the brain of animals lacking CNS AM contain hyperpolymerized tubulin, a consequence of AM downregulation. Behavioral analysis shows that mice with no AM in their brain have impaired motor coordination and are hyperactive and overanxious when compared to their wild-type littermates. Treatment with methylphenidate, haloperidol, and diazepam did not show differences between genotypes. Circulating levels of adrenocorticotropic hormone and corticosterone were similar in knockout and wild-type mice. Animals with no brain AM were less resistant to hypobaric hypoxia than wild-type mice, demonstrating the neuroprotective function of AM in the CNS. In conclusion, AM exerts a beneficial action in the brain by maintaining homeostasis both under normal and stress conditions. A drenomedullin (AM) is a 52-aa regulatory peptide with structural homology to calcitonin gene-related peptide (CGRP) and amylin. The adm gene is located in mouse chromosome 7 and codes for a preprohormone which, after posttranslational modifications, generates 2 biologically active peptides, AM and proadrenomedullin N-terminal 20 peptide (PAMP). Expression of these peptides is widespread and several functions have been ascribed to these molecules, including vasodilatation, bronchodilatation, hormone secretion regulation, growth modulation, angiogenesis promotion, and antimicrobial activity, among others (1). The receptor system for AM consists of a heterodimer composed of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein (RAMP) type 2 or 3 (2).In the CNS, AM was initially found in the hypothalamus (3), but later on it became clear that this peptide is expressed throughout the whole brain (4). Components of the AM receptor system are also found in most areas of the brain (5), providing an anatomical basis for the implication of AM in brain physiology. Receptor autoradiography studies have shown that AM is able to bind to many areas of the brain, as well (6). Recently, a new member of the CGRP/AM peptide family, with a peptide sequence similar to AM but coded by a different gene, has been reported and named AM2 or intermedin. This peptide has similar actions and distribution in the brain to original AM (7).Several observations suggest that AM could act as a neurotransmitter or neuromodulator. For instance, direct injection of AM in the CNS induces vasoconstriction (8), an incre...

Lack of adrenomedullin affects growth and differentiation of adult neural stem/progenitor cells

“…Previous studies have shown that a reduction in adm expression results in microtubule hyperpolymerization and higher levels of glu-tubulin in the cell (Sackett et al 2008;Fernandez et al 2008). To check whether this was also the case in aOBSCs, cells from both genotypes were stained with markers for glu-tubulin and the actin cytoskeleton ( Fig.…”

“…1) and crossing these animals with transgenic mice that expressed Cre recombinase under the tubulin Tα-1 promoter (Fernandez et al 2008). Heterozygote (w/f Cre + ) mice were crossed and their offspring were genotyped by the polymerase chain reaction (PCR) with tail clip DNA.…”

“…Taking advantage of our recently reported brain conditional knockout (KO) for adm (Fernandez et al 2008), we have studied the consequences of adm deletion in NSPC isolated from adult mouse olfactory bulb. These include changes in proliferation and in differentiation rates of the progeny of cultured neurospheres.…”

Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

“…In that regard, it was recently suggested that vascular damage may be the cause of vascular senescence. 26,27 To test whether these phenomena indicate accelerated senescence, we next evaluated aged conventional RAMP2 KO mice (RAMP2 +/− ). At 2 years of age, RAMP2 +/− mice showed inflammatory cell infiltration of the main organs ( Figure 2G-2I).…”

Association of a functional polymorphism in the adrenomedullin gene (ADM) with response to paroxetine

“…Conversely, mice lacking Adm in the brain show overanxious behaviour. 35 Differential expression of ADM has been observed in schizophrenia, 36 and ADM levels have been associated with mood and other psychiatric disorders. [19][20][21] Thus, the biological relevance and the relatively high expression change of Adm in response to paroxetine persuaded us to choose the human homologue of Adm as a candidate gene for genetic association studies in depressed individuals.…”