| First Author | Seo J | Year | 2014 |
| Journal | Cell | Volume | 157 |
| Issue | 2 | Pages | 486-498 |
| PubMed ID | 24725413 | Mgi Jnum | J:208030 |
| Mgi Id | MGI:5560492 | Doi | 10.1016/j.cell.2014.01.065 |
| Citation | Seo J, et al. (2014) Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Abeta-Induced Cognitive Impairment. Cell 157(2):486-98 |
| abstractText | Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIalpha-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Deltap35KI) to prevent p25 generation. The Deltap35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Deltap35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of beta-amyloid (Abeta)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Abeta-associated neurotoxicity and AD-like pathology. |
