Abstracts

Rationale: Distinct types of GABAergic inhibitory interneurons (INs) have different, sometimes paradoxical roles in the generation, maintenance, and termination of epileptiform activity. Impaired inhibition is a key pathomechanism of epilepsy, contributing to both seizures and comorbid cognitive deficits. Perisomatic inhibition by basket cells controls the rate and synchrony of the firing of excitatory neurons. The two types of basket cells, expressing either cholecystokinin (CCK) or parvalbumin (PV), are equally abundant and are both preserved in chronic epilepsy. Whether these two cell types have similar or different effects in controlling epileptic network activity is poorly understood. We used a chronic model of temporal lobe epilepsy (TLE) to assess the relative activity patterns of CCK- and PV-expressing interneurons during spontaneous epileptiform activity in awake, drug-free mice.

Methods: Double transgenic mice, PV-Cre x Sncg-Flp, on the C57BL/6J background, of both sexes, were used at 3-5 months of age. Epilepsy was induced by a single intrahippocampal kainate injection (70 nl, 20 mM). Control mice were either injected with saline or received no injection. Genetically encoded calcium indicators (Cre-dependent jRGECO1a and Flp-dependent GCaMP6s) were virally expressed in the contralateral dorsal CA1 to label PV- and CCK-expressing cells, respectively. A bipolar electrode and an imaging window (3 mm diameter, glass bottom) were implanted to allow local field potential recording (LFP) and calcium imaging, respectively. In vivo recordings were carried out in the chronic phase (2 months after kainate injection). Recurrent seizures were recorded using video-EEG monitoring in the home cage. Dual-channel two-photon calcium imaging was carried out in head-fixed mice on a linear treadmill.

Results: In control non-epileptic mice, natural transitions between theta- and sharp wave-ripple oscillations occurring during running and resting recruited CCK and PV IN activation in a diametrically opposed manner. While PV INs were activated during theta- and SWR episodes, CCK INs were activated during irregular activity in between. Moreover, CCK and PV IN activities were negatively correlated both across and within brain states. In chronic epileptic mice, the overall negative correlation between CCK and PV IN activities persisted. The opposite recruitment of CCK and PV-expressing cells was observed during spontaneously recurring pathological high-frequency oscillations and interictal spikes.

Conclusions: The diametrically opposed activity patterns of CCK- and PV IN populations both in control and epileptic mice suggest that the circuit mechanisms underlying their negative correlation remain functional in chronic epilepsy. Previous studies suggest that a mutual disinhibitory connectivity (PV to CCK and CCK to PV) may be a key mechanism for the temporal segregation of PV and CCK IN activity. Therefore, exogenous activation of one basket cell type may generate paradoxical effects by suppressing the other. Considering such disinhibitory effects may help planning more efficient intervention strategies targeting the GABAergic system.

Funding: Please list any funding that was received in support of this abstract.: Supported by the NIH K99NS117795 (to B.D.) and NS99457 (to IS).