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Genetic deletion of Lsamp causes exaggerated behavioral activation in novel environments.

ABSTRACT: The limbic system-associated membrane protein (LAMP) is a GPI-anchored cell adhesion molecule expressed heavily in limbic and limbic-associated regions of the developing and adult brain. Experimental studies show that LAMP promotes the growth of limbic neurons and guides the projections of limbic fibers. In order to examine the functional consequences of disrupting limbic circuit assembly, we generated a mouse line in which the Lsamp gene encoding LAMP was deleted. Basic neuroanatomical organization and sensory and motor development are normal in Lsamp(-/-) mice. The most profound change in behavior in both male and female Lsamp(-/-) mice is a heightened reactivity to novelty exhibited in several behavioral tests. Lsamp(-/-) mice display hyperactivity in a novel arena and both sexes habituate to the same activity levels as their wild type littermates, but at different rates. In the elevated plus maze, Lsamp(-/-) mice exhibit increased total arm entries, with a bias towards the open arms; they spend more time in the open arms and have a substantial increase in the amount of risk assessment in unprotected areas of the maze. In the y-maze, Lsamp(-/-) mice exhibit characteristic hyperactivity and a decreased level of spontaneous alternation during the period when their novelty-induced hyperactivity is at its peak. We hypothesize that Lsamp(-/-) mice may not simply exhibit a decrease in anxiety, but may have a heightened, and possibly maladaptive, response to novel environmental stressors. Genetic deletion of Lsamp may thus cause circumscribed changes in the fine connectivity of specific circuits that underlie these behaviors.

SUBMITTER: Catania EH

PROVIDER: S-EPMC2275759 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Genetic deletion of Lsamp causes exaggerated behavioral activation in novel environments.

Catania Elizabeth Haldeman EH Pimenta Aurea A Levitt Pat P

Behavioural brain research 20071207 2

The limbic system-associated membrane protein (LAMP) is a GPI-anchored cell adhesion molecule expressed heavily in limbic and limbic-associated regions of the developing and adult brain. Experimental studies show that LAMP promotes the growth of limbic neurons and guides the projections of limbic fibers. In order to examine the functional consequences of disrupting limbic circuit assembly, we generated a mouse line in which the Lsamp gene encoding LAMP was deleted. Basic neuroanatomical organiza ...[more]

PMID: 18199495

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Project description:The tyrosine phosphatase SHP2, encoded by PTPN11, is required for the survival, proliferation and differentiation of various cell types. Germline activating mutations in PTPN11 cause Noonan syndrome, whereas somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumours. Recently, heterozygous inactivating mutations in PTPN11 were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, enchondromas, joint destruction and bony deformities. The detailed pathogenesis of this disorder has remained unclear. Here we use a conditional knockout (floxed) Ptpn11 allele (Ptpn11(fl)) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages and osteoclasts (lysozyme M-Cre; LysMCre) or in cathepsin K (Ctsk)-expressing cells, previously thought to be osteoclasts. LysMCre;Ptpn11(fl/fl) mice had mild osteopetrosis. Notably, however, CtskCre;Ptpn11(fl/fl) mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp, also known as Pthlh) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR) or mitogen-activated protein kinase kinase (MEK) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11(fl/fl) mice. Thus, in contrast to its pro-oncogenic role in haematopoietic and epithelial cells, Ptpn11 is a tumour suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.

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Genetic deletion of Lsamp causes exaggerated behavioral activation in novel environments.

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Genetic deletion of Lsamp causes exaggerated behavioral activation in novel environments.

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