Laminin-β1 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 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) 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.

A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1

“…One lab has produced mechanistic evidence for a role for laminin β1 in synaptic plasticity. Molecular mechanisms of learning and memory were investigated by gene manipulation in vivo in rat hippocampus in combination with water maze testing ( Yang et al, 2011 ). Maze learning decreased laminin β1, and conversely laminin β1 overexpression impaired maze performance.…”

Integrin α3 Is Required for Late Postnatal Stability of Dendrite Arbors, Dendritic Spines and Synapses, and Mouse Behavior

“…Laminins are canonical ECM integrin ligands and a subset of laminin chains is specific to integrin α3β1 (Belkin and Stepp, 2000; Nishiuchi et al, 2006). Several laminin subunit chains are expressed in the hippocampus (Chen et al, 2003; Indyk et al, 2003; Egles et al, 2007) where they influence synapse density and ultrastructure (Egles et al, 2007) and spatial learning in mice (Yang et al, 2011). Although Reelin conventionally signals through Dab1 (Dulabon et al, 2000; Niu et al, 2008) and Netrins are known to signal via Frazzled/DCC (Stanco et al, 2009; Qu et al, 2012), both proteins can also bind integrinα3β1 and thus are also candidates for initiating stabilization.…”

Laminins and their receptors in the CNS

“…These results suggest a neuroprotective role of laminins in neurodegeneration. In sharp contrast to these reports, one study reported that laminin‐β1 impaired spatial learning through inhibition of MAPK/ERK and serum and glucocorticoid‐regulated kinase 1 (SGK1) signalling (Yang et al ., ), suggesting a detrimental role of laminin‐β1 in neurodegeneration. This discrepancy may be explained by different experimental models and/or different functions of distinct laminin isoforms.…”