Authors :
Presenting Author: Sang-Hun Lee, PhD – Colorado State University
Young-Jin Kang, PhD – Research Scientist, Biomedical Sciences, Colorado State University; Bret Smith, PhD – Professor and Head, Biomedical Sciences, Colorado State University
Rationale:
Parvalbumin-positive (PV+) basket cells (PVBCs) are a major subtype of PV+ interneuron in the dentate gyrus. They provide perisomatic inhibition to prevent overexcitation and maintain the stability of the dentate gyrus circuits. We showed that excitation of PVBCs by granule cells of the dentate gyrus and PVBC-mediated feedback inhibition increase in a mouse model of posttraumatic epilepsy, despite in fact that action potential firing of PVBCs in the dentate gyrus is reduced (Kang et al., 2022). These results suggest that compensatory mechanisms of PVBC circuits develop in posttraumatic epilepsy to suppress seizures in the dentate gyrus. On the other hand, it is possible that increased PVBC mediated inhibition promotes seizures in the dentate gyrus due to abnormal GABAergic activity and other circuit mechanisms. In addition, it is unknown whether these changes in PVBC circuits are epilepsy-associated or model-specific. Therefore, we used the intrahippocampal kainate (IHK) mouse model of temporal lobe epilepsy (TLE) to determine 1) whether IHK mice develop PVBC-associated compensatory changes and 2) whether activation of PV+ interneurons prevent or promote electrographic seizures in the dentate gyrus.
Methods:
IHK mice showing at least one Racine Stage four to five seizures/day for three days at three to four weeks after IHK injection are referred to here as TLE mice. Hippocampal slices from TLE and sham control mice were used for whole-cell patch-clamp recordings four to five weeks after IHK or saline injection to determine intrinsic and synaptic properties of PVBCs in the dentate gyrus. Next, we employed a mouse line expressing channelrhodopsin2 in PV+ interneurons to determine whether overall PV+ interneuron mediated inhibition increases in TLE mice. Lastly, we performed video-EEG recordings from a mouse line expressing Gq-Designer Receptors Exclusively Activated by Designer Drugs in PV+ interneurons to determine the critical role of PV+ interneurons in electrographic seizures in the epileptic dentate gyrus.
Results:
Reduced frequency of action potential firing was detected in PVBCs from TLE mice, whereas these neurons also manifested increased frequency and larger amplitude spontaneous excitatory postsynaptic currents. Functionally, optogenetic activation of PV+ interneurons produced larger amplitude postsynaptic inhibitory currents in granule cells from TLE mice. Video-EEG recordings revealed that TLE mice showed spontaneous electrographic seizures in the dentate gyrus and that chemogenetic activation of PV+ interneurons in TLE mice prevented the electrographic seizures.
Conclusions:
Our results suggest not only that the compensatory changes in PVBC circuits
develop in the IHK mouse model of TLE, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for disinhibition to prevent seizures in acquired epilepsies.
Funding:
This study was supported by R01 NS092552 (to B.N.S.) and CVMBS Shared Research Program (to S.H.L.).