Suppression of neuronal p27 impairs cognitive function in middle-aged mice

Accumulating evidence indicates an important role of cyclin-dependent kinases (CDKs) in regulating neuronal function under physiological and pathological conditions. p27 Kip1 (p27) is a member of the Cip/Kip family of CDK inhibitors (CKIs) with emerging functions in neuron development, but its role in cognitive aging is not well defined. Here we generated a transgenic mouse model with p27 conditionally (post-developmental) suppressed in forebrain neurons. We found that suppression of neuronal p27 did not affect overall cognitive function in young (3–6 months old) mice, as assessed by novel object recognition and Morris water maze tasks. In comparison, middle-aged (10–12 months old) homozygous p27 mutant mice (p27 −/− ) showed impairment of cognitive function. Imaging studies further revealed increased dendritic spine density driven by elevated immature spine forms and reduced overall spine maturity in the aged p27 −/− mice. In addition, protein synthesis, postsynaptic density and mitochondrial ultrastructure remained unchanged with suppression of p27. These data indicate p27 as a key regulator of dendritic spine development and cognitive resilience during aging, suggesting a role of neuronal p27 in maintaining synaptic integrity and cognitive function. • Generation of transgenic mice with conditional knockout of neuronal p27. • Age-dependent impairment of cognitive function in p27 mutant mice. • Abnormally increased hippocampal dendritic spine density in middle-aged p27 mice.