Regulation of hippocampal and behavioral excitability by cyclin-dependent kinase 5

• Published in: PloS one Vol. 4; no. 6; p. e5808
• Main Authors: Hawasli, Ammar H, Koovakkattu, Della, Hayashi, Kanehiro, Anderson, Anne E, Powell, Craig M, Sinton, Christopher M, Bibb, James A, Cooper, Donald C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.06.2009; Public Library of Science (PLoS)
• Subjects: Alzheimer's disease; Alzheimers disease; Analysis; Animals; Anticonvulsants; Anticonvulsants - pharmacology; Aspartate; Aspartic acid; Behavior; Behavior, Animal; Behavioral plasticity; Brain; Calpain; Cognitive ability; Cyclin-dependent kinase 5; Cyclin-Dependent Kinase 5 - metabolism; Cyclin-Dependent Kinase 5 - physiology; D-aspartic acid; Electromyography - methods; Electrophysiology - methods; Epilepsy; Excitability; Excitation; Experiments; Gene Expression Regulation; Glutamic acid receptors; Hippocampal plasticity; Hippocampus; Hippocampus - metabolism; Internal medicine; Kinases; Magnesium; Magnesium - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; N-methyl-D-aspartate; N-Methyl-D-aspartic acid receptors; Nervous system diseases; Nervous System Diseases - metabolism; Neurological diseases; Neurological Disorders/Epilepsy; Neurons; Neuroscience; Neuroscience/Animal Cognition; Neuroscience/Behavioral Neuroscience; Neuroscience/Neurobiology of Disease and Regeneration; Neuroscience/Neuronal Signaling Mechanisms; Neurosciences; Neurotransmission; Pharmacology; Plasticity; Potentiation; Proline; Protein-serine/threonine kinase; Proteins; Psychiatry; Regulation; Rodents; Seizing; Seizures; Seizures (Medicine); Social interaction; Synaptic plasticity; Threonine; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005808

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 Mg(2+)-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.