Abstracts

Rationale: Brain injury is an etiological factor for temporal lobe epilepsy and can lead to memory and cognitive impairments. Although it has been established that brain injury leads to early and persistent changes in dentate excitability, the mechanisms underlying these changes are yet to be fully elucidated. In classic dentate projection neurons, granule cells, tonic GABA currents modulate neuronal excitability and are altered in animal models of epilepsy. However, whether brain injury leads to early changes in tonic GABA currents in granule cells is not known. Additionally, recent studies have characterized a novel class of projection neurons, semilunar granule cells (SGC) which, like granule cells, project to CA3 but have distinctive dendritic structure and physiology (Williams et al., 2007). Since SGCs have molecular layer axon collaterals and form an alternate dentate output, changes in SGC physiology following brain injury will influence overall dentate excitability and output. This study examined whether concussive brain injury alters granule cell and SGC synaptic and tonic GABA currents and SGC excitability. Methods: This study used lateral fluid percussion injury (FPI) in young adult rats to model brain injury in vivo. Whole-cell patch-clamp recording data from hippocampal slices in FPI and sham-injured rats were compared. Biocytin immunocytology was used for post-hoc cell identification. Results: One week after FPI, the amplitude of granule cell tonic GABA currents, measured as the baseline currents blocked by the GABAa receptor antagonist bicuculline (100 ?M), was significantly increased compared to sham-injured controls (in pA, CON: 8.4 1.1, n=11; FPI: 20.8 3.4, n=6, p < 0.01). The post-injury increase in granule cell tonic GABA currents returned to control levels 3 months after injury (in pA, CON: 9.4 3.1, n=6; FPI: 6.5 1.7, n=5, p> 0.05). Recordings from granule cells and SGCs in control rats showed that the two cell types differed in synaptic and tonic inhibitory current parameters. Spontaneous inhibitory synaptic currents (sIPSCs) in SGCs were smaller in amplitude but more frequent than in granule cells. The magnitude of tonic GABA currents in SGCs was significantly larger than in granule cells. The GABAa receptor antagonist, gabazine, enhanced the input resistance of SGCs indicating that tonic GABA currents contribute to the characteristic low input resistance that distinguishes SGCs from granule cells. In contrast to granule cells, the amplitude of tonic GABA currents in SGCs from head-injured rats was reduced one week after FPI. Additionally, after FPI, SGCs showed an increase in input resistance and firing in response to depolarizing current injections.Conclusions: These data are the first demonstration of early and opposite changes in tonic GABA currents in granule cells and SGCs after brain injury. Our results show post-injury increase in SGC excitability and suggest that SGCs may provide a focus for early dentate hyperexcitability after brain trauma.