Prolonged calcium flux following traumatic brain injury occurs via injury-induced molecular alterations in the NMDA receptor

A major contributor to the pathophysiology of traumatic brain injury (TBI) is ionic flux, with calcium playing a key role. Although calcium is known to accumulate in dying cells, experimental TBI is characterized by a prolonged, sublethal load of calcium in viable cells. While most neurons survive the initial injury, some enter a compromised state of “neuronal dysfunction” during which minor cellular stresses can lead to the cell's demise. To understand calcium's role in post-traumatic neuronal dysfunction, post-traumatic calcium accumulation needs to be thoroughly described and the underlying mechanism investigated.; The fluid percussion injury (FPI) device was used to induce mild-moderate TBI in rats at different stages of development—postnatal day 17 (P17), P28, and adult. 45Calcium autoradiographic studies revealed two patterns of 45Ca++ accumulation following FPI and their age-dependency: acute, diffuse calcium accumulation in the ipsilateral cortex (lasting at least two days in adult rats) associated with post-traumatic ionic flux and delayed, focal calcium accumulation in the ipsilateral thalamus reflecting cell death.; To investigate a possible mechanism of persistent post-traumatic calcium influx into viable cells, quantitative western blotting was performed on adult rat brain regions of interest using antibodies against NMDA receptor subunits. The ipsilateral parietal and occipital cortices, the same regions exhibiting prolonged 45Ca++ accumulation in the absence of cell death, demonstrated an acute reduction in the NR2A:NR2B relative ratio. Thus, TBI seems to regionally induce this sensitized form of the NMDA receptor, a major conduit of calcium flux.; The contribution of TBI-induced alterations in NMDA receptor subunit composition to post-traumatic calcium accumulation was investigated using two NMDA receptor antagonists-non-subunit-selective MK-801 and NR2B subunit-specific ifenprodil. Regions that shifted to a lower NR2A:NR2B relative ratio after FPI had a greater proportion of calcium flux occurring through NR2B-containing receptors. This not only indicates a functional significance of the NMDA receptor subunit alteration, but also suggests that the subunit shift contributes to post-traumatic calcium flux.; From these studies, it appears that a sublethal load of calcium occurs after a mild-moderate TBI and that an injury-induced alteration in the NMDA receptor subunit composition is a major contributor to this pathophysiology.