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Laminin-?1 impairs spatial learning through inhibition of ERK/MAPK and SGK1 signaling.

ABSTRACT: Laminin is a major structural element of the basal lamina consisting of an ?-chain, a ?-chain, and a ?-chain arranged in a cross-like structure, with their C-terminal inter-coiled. Laminin is abundantly expressed in the hippocampus of mature brain and is implicated in several psychiatric disorders, but its possible role involved in learning and memory function is not known. This issue was examined here. Our results revealed that water maze training significantly decreased laminin-?1 (LB1) expression in the rat hippocampal CA1 area. Transfection of LB1 WT plasmid to hippocampal CA1 neurons impaired water maze performance in rats. Meanwhile, it decreased the phosphorylation level of ERK/MAPK and protein kinase serum- and glucocorticoid-inducible kinase-1 (SGK1). By contrast, knockdown of endogenous LB1 expression using RNA interference (LB1 siRNA) enhanced water maze performance. Meanwhile, it increased the phosphorylation level of ERK/MAPK and SGK1. The enhancing effect of LB1 siRNA on spatial learning and on the phosphorylation of ERK/MAPK and SGK1 was blocked by co-treatment with the MEK inhibitor U0126 at a concentration that did not apparently affect spatial learning and ERK/MAPK phosphorylation alone. Further, the enhancing effect of LB1 siRNA on spatial learning and SGK1 phosphorylation was similarly blocked by co-transfection with SGK1 siRNA at a concentration that did not markedly affect spatial learning and SGK1 expression alone. These results together indicate that LB1 negatively regulates spatial learning in rats. In addition, LB1 impairs spatial learning through decreased activation of the ERK/MAPK-SGK1 signaling pathway in the rat hippocampus.

SUBMITTER: Yang YC

PROVIDER: S-EPMC3194083 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Laminin-β1 impairs spatial learning through inhibition of ERK/MAPK and SGK1 signaling.

Yang Ying C YC Ma Yun L YL Liu Wen T WT Lee Eminy H Y EH

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110817 12

Laminin is a major structural element of the basal lamina consisting of an α-chain, a β-chain, and a γ-chain arranged in a cross-like structure, with their C-terminal inter-coiled. Laminin is abundantly expressed in the hippocampus of mature brain and is implicated in several psychiatric disorders, but its possible role involved in learning and memory function is not known. This issue was examined here. Our results revealed that water maze training significantly decreased laminin-β1 (LB1) expres ...[more]

PMID: 21849984

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Project description:BackgroundThe skin is largely comprised of keratinocytes within the interfollicular epidermis. Over approximately two weeks these cells differentiate and traverse the thickness of the skin. The stage of differentiation is therefore reflected in the positions of cells within the tissue, providing a convenient axis along which to study the signaling events that occur in situ during keratinocyte terminal differentiation, over this extended two-week timescale. The canonical ERK-MAPK signaling cascade (Raf-1, MEK-1/2 and ERK-1/2) has been implicated in controlling diverse cellular behaviors, including proliferation and differentiation. While the molecular interactions involved in signal transduction through this cascade have been well characterized in cell culture experiments, our understanding of how this sequence of events unfolds to determine cell fate within a homeostatic tissue environment has not been fully characterized.MethodsWe measured the abundance of total and phosphorylated ERK-MAPK signaling proteins within interfollicular keratinocytes in transverse cross-sections of human epidermis using immunofluorescence microscopy. To investigate these data we developed a mathematical model of the signaling cascade using a normalized-Hill differential equation formalism.ResultsThese data show coordinated variation in the abundance of phosphorylated ERK-MAPK components across the epidermis. Statistical analysis of these data shows that associations between phosphorylated ERK-MAPK components which correspond to canonical molecular interactions are dependent upon spatial position within the epidermis. The model demonstrates that the spatial profile of activation for ERK-MAPK signaling components across the epidermis may be maintained in a cell-autonomous fashion by an underlying spatial gradient in calcium signaling.ConclusionsOur data demonstrate an extended phospho-protein profile of ERK-MAPK signaling cascade components across the epidermis in situ, and statistical associations in these data indicate canonical ERK-MAPK interactions underlie this spatial profile of ERK-MAPK activation. Using mathematical modelling we have demonstrated that spatially varying calcium signaling components across the epidermis may be sufficient to maintain the spatial profile of ERK-MAPK signaling cascade components in a cell-autonomous manner. These findings may have significant implications for the wide range of cancer drugs which therapeutically target ERK-MAPK signaling components.

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Laminin-?1 impairs spatial learning through inhibition of ERK/MAPK and SGK1 signaling.

Publications

Laminin-β1 impairs spatial learning through inhibition of ERK/MAPK and SGK1 signaling.

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