Our lab studies the function of cyclin-dependent kinase 5 (Cdk5) in neuronal development and neurodegeneration. Recent evidence suggests an additional role for Cdk5 in synaptic plasticity and learning and memory. Cdk5 is activated through binding to its neuronal-specific activator p35. Studies up until this point have shown that neurotoxic conditions result in the cleavage of p35 into p25 in vitro and subsequent cell death. Moreover, overexpression of p25 in vitro and in vivo, have been associated with neuronal cell death and brain atrophy, suggesting that overactivation of Cdk5 by p25 is detrimental. We now have novel data that chemical induction of long-term potentiation (LTP) can generate p25 without resulting in cell death. The experiments outlined herein seek to address the relationship between p25 production through LTP induction and synaptic plasticity using both in vitro and in vivo studies. Additionally, we are generating a knock-in mouse model which expresses a mutant form of p35 that is resistant to calpain-mediated cleavage to better address the physiological functions of p35 and p25 in neurodegeneration, synaptic plasticity and learning and memory. These experiments have the potential of enhancing our understanding of the molecular events involved in neurodegeneration, synaptic plasticity and learning and memory, and could lead to the development of new therapies.
| Seo, Jinsoo; Giusti-Rodríguez, Paola; Zhou, Ying et al. (2014) Activity-dependent p25 generation regulates synaptic plasticity and A?-induced cognitive impairment. Cell 157:486-498 |
| Giusti-Rodríguez, Paola; Gao, Jun; Gräff, Johannes et al. (2011) Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of ?-secretase (BACE1). J Neurosci 31:15751-6 |
