Abstracts

Rationale: Inhibitory neurons of the dentate gyrus are crucial in maintaining the functional “gate” that controls the spread of network excitability in the trisynaptic circuit. Specifically, parvalbumin-positive chandelier cells (PV-ChCs), frequently located in the inner molecular layer, regulate granule cell firing by synaptic inhibition of the axon initial segment. Circuit effects of PV-ChCs are likely distinct from PV-basket cells (PV-BCs) which underlie somatic feed-forward and feedback inhibition. In the human epileptic hippocampus, specifically in dentate, it was shown that axonal cartridges of chandelier cell subtype undergo reorganization. Recent studies indicate an excitatory role of chandelier cells in cortical networks, however, how dentate PV-ChCs regulate granule cell excitability in normal circuits and if this effect is modified after experimental status epilepticus (SE) is not known. Therefore, we examined whether PV-ChCs undergo early post-SE changes which could undermine granule cell inhibition after experimental SE. Methods: Adult mice (6-10 week) expressing EYFP in PV-expressing neurons (Jackson labs: 008069) were treated with pilocarpine to induce (SE). Whole-cell patch clamp recordings were obtained from EYFP positive cells in the inner molecular layer in hippocampal sections prepared from mice one week after SE (post-SE) and in age-matched saline-injected and naive controls. Cells were filled with biocytin during recordings and processed to reveal morphology. PV-ChCs were distinguished from PV-BCs by the presence of vertical axonal cartridges. Results: One week after SE, PV-ChCs showed a significant decrease in firing rate in response to somatic current injection compared to controls (somatic Iinj 800pA: Control: 200.0±32.9 Hz, n=6; post-SE: 104.8±14.2 Hz, n=12, p < 0.05 by Two-way RM ANOVA). However, active and passive properties such as input resistance, Sag ratio, and action potential threshold in PV-ChCs were not altered early after SE. The post-SE alterations in intrinsic physiology are unique to PV-ChCs and were not observed in PV-BCs (Yu et al., 2015). Consistent with findings in PV-BCs, the frequency (Control: Median=14.5Hz; IQR=6.8-30.2, n=7; Post-SE: Median=6.1Hz; IQR=2.4-11.4, n=8, p < 0.05 by K-S test) and amplitude of spontaneous inhibitory synaptic currents in PV-ChCs were decreased early after SE. Similarly, spontaneous excitatory synaptic currents (sEPSCs) in PV-ChCs early after SE, show a decrease in the frequency (Control: Median=12.1Hz; IQR=5.6-21.3, n=8; Post-SE: Median=6.8Hz; IQR=2.5-23.8, n=6 by K-S test) while the amplitude of sEPSCs show significant increase. Conclusions: Together, our findings suggest that in addition to a robust decrease in intrinsic excitability, PV-ChCs also show a reduction in the frequency of postsynaptic excitatory and inhibitory currents, which suggests impairment in the recruitment of PV-ChCs in feed-forward inhibition of dentate granule cells which could undermine the inhibitory dentate gate in the latent period after seizures. Funding: Support: : NIH/NINDS R01 NS069861 (V.S)