Figure 2.

Our proposed acute injury response (AIR) mechanism outlining reactive signaling to an acute, brief seizure or acute, mild TBI. This mechanism shunts cellular signaling away from pro-death response pathways and toward cellular protection, with the goals of restoring the balance between glutamate release and reuptake, intracellular Ca²⁺-driven ER stress responses, and apoptotic-necrotic dynamics. In response to acute injury, caspase-1 cleaves IL-1 precursors, resulting in IL-1β formation. IL-1β unselectively up-or down-regulates glutamate receptor subunit densities, resulting in an acute disruption of balanced glutamate release and reuptake. There is increased CaMK-II activation that promotes increased glutamate release (102, 103). Unselective CaMK-II phosphorylation and autophosphorylation occurs at upregulated AMPA-GluR1 (104) but not at down-regulated NMDA-R2B (105), resulting in increased AMPA-GluR1 Ca2+ influx/channel conductance and decreased NMDA-NR2B Ca2+ influx/channel conductance, respectively. However, CaMK-II also recruits astrocytes into the affected region (59, 60, 106, 107). Increased astrocytes/IL-1 receptor density aid in clearing excess glutamate and ILs, inhibiting further glutamate release, thereby limiting excitotoxic propagation. (1) = Neuronal membrane, (2) = Synaptic cleft, (3) = CaMK-II autophosphorylation, (4) = CaMK-II-Glutamate receptor phosphorylation. Red = Excitotoxic signaling, Green = Neuroprotective signaling. X = response reduction/down-regulation.