Regulation of Excitatory Neurotransmission, Synaptic Plasticity, and Learning by Cyclin-Dependent Kinase 5
| dc.contributor.advisor | Bibb, James A. | en |
| dc.creator | Hawasli, Ammar Hamami | en |
| dc.date.accessioned | 2010-07-12T17:33:29Z | |
| dc.date.available | 2010-07-12T17:33:29Z | |
| dc.date.issued | 2009-06-17 | |
| dc.description.abstract | Cyclin-dependent kinase 5 has been implicated in many physiological and pathological processes in the central nervous system. To better understand Cyclin-dependent kinase 5's roles in the adult brain, we developed and studied several conditional Cyclin-dependent kinase 5 knockout model systems. Soon after conditional loss of Cyclin-dependent kinase 5, mice displayed improved hippocampal learning and enhanced synaptic plasticity in the hippocampal Schaffer collateral pathway. The genetically enhanced mice displayed increased N-methyl-D-aspartate receptor-mediated currents and elevated levels of the NR2B N-methyl-D-aspartate receptor subunit. The enhancement in synaptic plasticity was directly attributed to the increased current through NR2B-containing receptors. NR2B levels were elevated in Cyclin-dependent kinase 5 knockout mice due to an impairment in the calpain-mediated degradation of NR2B. Consistently, Cyclin-dependent kinase 5 directly facilitated the degradation of NR2B cytoplasmic-tail in vitro. Cyclin-dependent kinase 5, NR2B, and calpain coimmunoprecipitated in vivo and directly bound one another in vitro. NR2B inhibited Cyclin-dependent kinase 5 activity in vitro, indicating a potential feedback mechanism. These findings suggested that Cyclin-dependent kinase 5 interacts directly with NR2B and calpain to facilitate the degradation of NR2B, thereby attenuating synaptic plasticity. In addition to regulating functional plasticity, Cyclin-dependent kinase 5 also plays roles in structural plasticity and presynaptic function. Cyclin-dependent kinase 5 facilitated the calpain-mediated degradation of spectrin in vitro. Spectrin degradation and depolymerized actin levels were decreased in conditional Cyclin-dependent kinase 5 knockout hippocampus. These results implicate Cyclin-dependent kinase 5 dendritic in spine dynamics which is critical for synaptic plasticity. Loss of Cyclin-dependent kinase 5 also led to a presynaptic enhancement in post-tetanic potentiation and a deficit in paired-pulse facilitation, which are consistent with an increase in probability of synaptic vesicle release, due to increased numbers of vesicles in the readily releasable pool or altered sensitivity to presynaptic calcium. Finally, chronic Cyclin-dependent kinase 5 loss produced increases in behavioral and neuronal excitability followed by electrographic abnormalities in vivo and reduced brain weight. These findings suggest that the enhancement in excitatory neurotransmission which initially led to improvements in learning and plasticity preceded excessive excitability and subsequent neuropathology. Consequently, Cyclin-dependent kinase 5 regulates excitatory neurotransmission, synaptic plasticity. | en |
| dc.format.digitalOrigin | born digital | en |
| dc.format.medium | Electronic | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 754186182 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/317 | |
| dc.language.iso | en | en |
| dc.subject | Behavior and Behavior Mechanisms | en |
| dc.subject | Cyclin-Dependent Kinase 5 | en |
| dc.subject | Brain | en |
| dc.subject | Synaptic Transmission | en |
| dc.title | Regulation of Excitatory Neurotransmission, Synaptic Plasticity, and Learning by Cyclin-Dependent Kinase 5 | en |
| dc.type | Thesis | en |
| dc.type.genre | dissertation | en |
| dc.type.material | Text | en |
| thesis.date.available | 2011-06-17 | |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Neuroscience | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |