Traumatic brain injury (TBI) produces an acute phase of neuronal excitation followed by a chronic phase of depressed neuronal function. Alterations in excitatory and inhibitory receptor interactions may be dynamically involved in subsequent long-term detriments in neuronal and cognitive functioning. TBI- induced elevations in intracellular calcium concentrations ([Ca2+]i) are mediated primarily by the NMDA receptor. Elevated [Ca2+]i may trigger intracellular mechanisms which drive changes in GABA-A receptor protein synthesis and expression, ultimately resulting in receptor dysfunction.
Western blot analysis was used to investigate alterations to GABA-A receptor subunits α1 and β33 in the hippocampus of rats 3 hours, 24 hours, or 7 days following TBI. No injury- induced alterations in protein expression were found for the β3 subunit, which in the hippocampus is primarily located on principal neurons (i.e., pyramidal and granule cells). No significant alterations to the α1 receptor were found 3 hours following TBl, but a significant increase in α1 protein was found 24 hours post- injury, and this increase persisted for at least 7 days. GABA-A receptors containing the α1 subunit are primarily located on interneurons, implying a potential strengthening of interneuron-mediated inhibitory tone during the chronic phase of TBI.
Study 2 used pre-injury injections of MK-801 (0.3 mg/kg) to block calcium influx through the NMDA receptor. This treatment normalized α1 protein expression 24 hours following injury (the time point of greatest change in study 1). NMDA-mediated calcium influx may, therefore, be responsible for triggering the cascade that results in increased GABA-A receptor α1 protein expression chronically following TBI.
These studies demonstrate that TBl produces an increase in GABA-A receptor α1, but not β3, subunits 24 hours and 7 days post-injury. The differential directions of the subunit changes may indicate a strengthening of inhibitory tone during the chronic phase of TBI, a period characterized by a depression of neuronal function. Although the exact mechanism of change to the α1 subunit is unknown, study 2 indicates that it is driven by NMDA-mediated elevations in [Ca2+]i. The functional consequences of increased inhibitory tone may contribute to long-term detriments in cognitive and behavioral outcome following injury.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-5783 |
| Date | 01 January 2001 |
| Creators | Gibson, Cynthia J. |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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