Opposing Modifications in Intrinsic Currents and Synaptic Inputs in Post-Traumatic Mossy Cells: Evidence for Single-Cell Homeostasis in a Hyperexcitable Network

Abstract

Recent experimental and modeling results demonstrated that surviving mossy cells in the dentate gyrus play key roles in the generation of network hyperexcitability. Here we examined if mossy cells exhibit long-term plasticity in the posttraumatic, hyperexcitable dentate gyrus. Mossy cells 1 wk after fluid percussion head injury did not show alterations in their current-firing frequency (I-F) and current-membrane voltage (I-V) relationships. In spite of the unchanged I-F and I-V curves, mossy cells showed extensive modifications in Na(+), K(+) and h-currents, indicating the coordinated nature of these opposing modifications. Computational experiments in a realistic large-scale model of the dentate gyrus demonstrated that individually, these perturbations could significantly affect network activity. Synaptic inputs also displayed systematic, opposing modifications. Miniature excitatory postsynaptic current (EPSC) amplitudes were decreased, whereas miniature inhibitory postsynaptic current (IPSC) amplitudes were increased as expected from a homeostatic response to network hyperexcitability. In addition, opposing alterations in miniature and spontaneous synaptic event frequencies and amplitudes were observed for both EPSCs and IPSCs. Despite extensive changes in synaptic inputs, cannabinoid-mediated depolarization-induced suppression of inhibition was not altered in posttraumatic mossy cells. These data demonstrate that many intrinsic and synaptic properties of mossy cells undergo highly specific, long-term alterations after traumatic brain injury. The systematic nature of such extensive and opposing alterations suggests that single-cell properties are significantly influenced by homeostatic mechanisms in hyperexcitable circuits.

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

“…The threshold for the first action potential was determined by calculating the first time derivative (dV/dt) of the voltage trace and setting 30 mV/ms as the threshold level for action potential initiation. The membrane voltage at the time when dV/dt value crossed 30 mV/ms was measured as the action potential threshold (Cooper et al, 2003;Howard et al, 2007). Spike frequency adaptation ratio was calculated as the ratio of the interspike interval between the first two and last two spikes in response to a ϩ200 pA current injection for 1 s. In SGCs, the input resistance was determined from the slope of linear fits to the steady-state voltage responses during current injections in the range of Ϫ200 -0 pA (in 40 pA steps).…”

“…Notably, as illustrated by the membrane voltage traces in Figure 3, C and D, FPI SGCs showed greater hyperpolarization in response to a Ϫ120 pA current injection compared with sham-injured SGCs. Accordingly, the input resistance of FPI SGCs was greater than in sham-injured SGCs ( of granule cells and mossy cells undergo profound posttraumatic modifications (Santhakumar et al, 2001;Howard et al, 2007;Mtchedlishvili et al, 2010). Curiously, despite postinjury hilar interneuronal loss and a corresponding decrease in action potential-independent mIPSCs, the frequency of spontaneous IPSCs in granule cells and mossy cells is elevated following FPI (Santhakumar et al, 2001;Howard et al, 2007).…”

“…Although increases in excitability of granule cells or mossy cells are potential direct mechanisms to account for post-traumatic increases in dentate field excitability, little postinjury change in firing has been found in these two dentate glutamatergic neurons (Santhakumar et al, 2000;Howard et al, 2007). We examined whether the excitability of SGCs, a population of neurons originally described by Ramó n y Cajal (1995) and recently characterized as glutamatergic dentate projection neurons (Williams et al, 2007), is altered after brain injury.…”

“…Accordingly, the input resistance of FPI SGCs was greater than in sham-injured SGCs ( of granule cells and mossy cells undergo profound posttraumatic modifications (Santhakumar et al, 2001;Howard et al, 2007;Mtchedlishvili et al, 2010). Curiously, despite postinjury hilar interneuronal loss and a corresponding decrease in action potential-independent mIPSCs, the frequency of spontaneous IPSCs in granule cells and mossy cells is elevated following FPI (Santhakumar et al, 2001;Howard et al, 2007). Increased excitability of certain interneurons and enhanced excitatory drive to surviving interneurons after brain injury may contribute to an increase in sIPSC frequency following brain injury Santhakumar et al, 2001;Hunt et al, 2011).…”

“…Although brain injury leads to neuronal damage and enhanced excitability of the dentate gyrus within 1 week after trauma (Lowenstein et al, 1992;Toth et al, 1997), intrinsic excitability of the major glutamatergic neurons remains unchanged (Santhakumar et al, 2000;Howard et al, 2007). However, whether hyperexcitability of a subset of glutamatergic neurons may underlie early postinjury increases in dentate excitability is not known.…”