Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway

Ji-Song Guan,Li-Huei Tsai,Steven A Carr,Ying Zhou,Lei Zhang,Karl R Clauser,J Julius Zhu,Omer Durak,Jun Gao,Nadine Joseph,Susan C Su,Zhigang Xie,Brahim Nait-Oumesmar

doi:10.1371/journal.pone.0025735

Abstract

Memory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.

Highlights

The hippocampus is considered to be a key region for long-term memory formation in humans and rodents [1,2], yet the molecular mechanisms underlying memory formation are still not fully understood
CyclinDependent Kinase 5 (Cdk5) is thought to be involved in the morphogenesis of synaptic connections, as well as in the regulation of synaptic transmission, through interactions at both presynaptic terminals and postsynaptic spines with proteins that include postsynaptic density (PSD)-95 [39], ErbB [40], Stat3 [41], DARPP-32 [42], CASK [43], and Eph4/ephexin1
In contrast to an earlier study by Hawasli et al in which enhanced hippocampal synaptic plasticity and spatial learning behaviors were observed due to upregulated NMDA receptor subunit NR2B levels [23], we find that the neuron-specific Cdk5 loss of function has a detrimental effect on hippocampaldependent associative and spatial memory, and impairs synaptic plasticity, but leads to unaltered NR2B levels

Summary

Introduction

The hippocampus is considered to be a key region for long-term memory formation in humans and rodents [1,2], yet the molecular mechanisms underlying memory formation are still not fully understood. The PKC gamma mutant mouse, which displays normal LTD and impaired LTP, exhibits a relatively mild behavioral deficit [8] Both forms of synaptic plasticity (LTD and LTP) are required for memory formation. Accumulating data regarding the molecular events underlying CREB-dependent learning and memory in Drosophila, mice, and rats all indicate that CREB activation by phosphorylation at the Serine 133 residue is required for the maintenance of LTP and formation of long-term memory [10]. The observed deficiencies in Cdk conditional knockout mice can be rescued by rolipram treatment Taken together, these results indicate a key function for Cdk in regulating cAMP signaling via modulation of PDE expression to facilitate synaptic plasticity and hippocampaldependent memory formation

Results

Discussion

Materials and Methods