Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory.
While deregulation of cyclin-dependent kinase 5 (Cdk5) has been implicated in neurodegenerative diseases, its precise role in synaptic plasticity and memory remains elusive. Proteolytic cleavage of p35, a regulatory subunit of Cdk5, by calpain results in the generation of the truncated p25 protein, which causes hyperactivation of Cdk5. Using region-specific and inducible transgenic mice, we show that transiently increased p25 expression in the hippocampus enhanced long-term potentiation (LTP) and facilitated hippocampus-dependent memory. Moreover, p25 expression increased the number of dendritic spines and synapses. Importantly, enhanced memory achieved by a transient expression of p25 followed by its repression did not cause neurodegeneration. In contrast, prolonged p25 production caused severe cognitive deficits, which were accompanied by synaptic and neuronal loss and impaired LTP. Our data suggest a role for p25 in synaptic plasticity, synaptogenesis, learning, and memory and provide a model whereby deregulation of a plasticity factor can contribute to neurodegeneration.
Fischer
Andre
A
Harvard Medical School, Department of Pathology, Boston, Massachusetts 02115, USA.
Sananbenesi
Farahnaz
F
Pang
Petti T
PT
Lu
Bai
B
Tsai
Li-Huei
LH
D000818:Animals; D001007:Anxiety; D001245:Association Learning / Q000502:physiology; D003072:Cognition Disorders / Q000209:etiology; D003213:Conditioning, Psychological; D003712:Dendrites / Q000502:physiology / Q000648:ultrastructure; D005239:Fear / Q000523:psychology; D006624:Hippocampus / Q000502:physiology*; D007858:Learning / Q000502:physiology; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D010770:Phosphotransferases; D013028:Space Perception / Q000502:physiology; D013550:Swimming; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D013997:Time Factors
C492236:Cdk5r1 protein, mouse; D009419:Nerve Tissue Proteins; D010770:Phosphotransferases