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. p27Kip1 (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.