Abstract
Environment enrichment (EE) has a variety of effects on brain structure and function. Brain-derived neurotrophic factor (BDNF) is essential for EE-induced hippocampal neurogenesis and memory enhancement. However, the intracellular pathway downstream of BDNF to modulate EE effects is poorly understood. Here we show that integrin-linked kinase (ILK) levels are elevated upon EE stimuli in a BDNF-dependent manner. Using ILK-shRNA (siILK) lentivirus, we demonstrate that knockdown of ILK impairs EE-promoted hippocampal neurogenesis and memory by increasing glycogen synthase kinase-3β (GSK3β) activity. Finally, overexpressing ILK in the hippocampus could rescue the neurogenesis and memory deficits in BDNF+/− mice. These results indicate that ILK is indispensable for BDNF-mediated hippocampal neurogenesis and memory enhancement upon EE stimuli via regulating GSK3β activity. This is a new insight of the precise mechanism in EE-enhanced memory processes and ILK is a potentially important therapeutic target that merits further study.
Highlights
Environment enrichment (EE) has a variety of effects on brain structure and function
Increased integrin-linked kinase (ILK) expression was responsible for EE-induced hippocampal neurogenesis and memory improvement by inhibiting glycogen synthase kinase-3β (GSK3β) activity
ILK is a serine/threonine protein kinase widely expressed in various brain regions[22], which kinase activity is stimulated by integrins, growth factors and chemokines[41,42,43]
Summary
Immunohistological staining was performed on free-floating sections and stained in a solution containing 0.1% BSA, 0.3% Triton X-100, 10% normal goat serum, and anti-ILK mice primary antibody (Sigma, 1:200), anti-GFAP rabbit primary anibody (Millipore, 1:1000). After a series of 0.1 M phosphate buffer washes, sections were stained by using the same blocking solution as above and Alexa Fluor 488 goat anti-mice and 594 goat anti-rabbit secondary antibody (Inventrogen, 1:1000). After blocking with 10% donkey serum in PBS containing 0.3% Triton X-100 for 1 h, sections were incubated with primary antibodies to BrdU (Abcam, 1:1000) and NeuN (Millipore, 1:1000) overnight at 4 °C, followed by Alexa Fluor secondary antibodies for 1 h. To analyze cell proliferation in animals, they were injected with BrdU (Sigma, 50 mg/kg, i.p.) in 0.9% NaCl solution, and were perfused 2 h later. Data analyses were performed using SPSS statistical program, version 13.0
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