Regulation of Hippocampal and Behavioral Excitability by Cyclin-Dependent Kinase 5

Ammar H Hawasli,Christopher M Sinton,Kanehiro Hayashi,Anne E Anderson,Della Koovakkattu,Donald C Cooper,James A Bibb,Craig M Powell,Vladimir Brezina

doi:10.1371/journal.pone.0005808

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that has been implicated in learning, synaptic plasticity, neurotransmission, and numerous neurological disorders. We previously showed that conditional loss of Cdk5 in adult mice enhanced hippocampal learning and plasticity via modulation of calpain-mediated N-methyl-D-aspartic acid receptor (NMDAR) degradation. In the present study, we characterize the enhanced synaptic plasticity and examine the effects of long-term Cdk5 loss on hippocampal excitability in adult mice. Field excitatory post-synaptic potentials (fEPSPs) from the Schaffer collateral CA1 subregion of the hippocampus (SC/CA1) reveal that loss of Cdk5 altered theta burst topography and enhanced post-tetanic potentiation. Since Cdk5 governs NMDAR NR2B subunit levels, we investigated the effects of long-term Cdk5 knockout on hippocampal neuronal excitability by measuring NMDAR-mediated fEPSP magnitudes and population-spike thresholds. Long-term loss of Cdk5 led to increased Mg2+-sensitive potentials and a lower threshold for epileptiform activity and seizures. Biochemical analyses were performed to better understand the role of Cdk5 in seizures. Induced-seizures in wild-type animals led to elevated amounts of p25, the Cdk5-activating cofactor. Long-term, but not acute, loss of Cdk5 led to decreased p25 levels, suggesting that Cdk5/p25 may be activated as a homeostatic mechanism to attenuate epileptiform activity. These findings indicate that Cdk5 regulates synaptic plasticity, controls neuronal and behavioral stimulus-induced excitability and may be a novel pharmacological target for cognitive and anticonvulsant therapies.

Highlights

Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/ threonine protein kinase, and its neuronal-specific activating cofactors have been implicated in numerous physiological and pathological processes in the mammalian nervous system [1,2,3,4,5,6,7,8,9,10,11,12,13,14]
Cdk5 KO mice displayed a reduced threshold for LTP induction (Figure 1B) [7]. To determine if this enhancement was due to increased responsiveness during the theta burst stimulation (TBS) used to induce LTP we examined the Field excitatory post-synaptic potentials (fEPSPs) during TBS
Cdk5 has been implicated in exocytosis and endocytosis via phosphorylation of numerous substrates including synapsin, amphiphysin I, dynamin, and others [44,45,46,47]

Summary

Introduction

Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/ threonine protein kinase, and its neuronal-specific activating cofactors have been implicated in numerous physiological and pathological processes in the mammalian nervous system [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Cdk has been implicated in hippocampal learning and synaptic plasticity [5,7,10,15,16,17] and the pathogenesis of neurodegenerative disorders, such as Alzheimer’s disease and neuropsychiatric illnesses, such as addiction [2,15,18,19]. We previously reported that Cdk controls hippocampusdependent learning and synaptic plasticity [7]. The enhancement in synaptic plasticity was due to increased NMDAR-mediated currents secondary to elevated surface expression of NR2B. Cdk was shown to facilitate the calpain-mediated degradation of NR2B upon activation of NMDARs. The regulation of NMDAR degradation appears to play a critical role in synaptic plasticity [20]

Methods

Results

Conclusion