Breakdown of spatial coding and neural synchronization in epilepsy

Abstract

Temporal lobe epilepsy causes significant cognitive deficits in both human patients and rodent models, yet the specific circuit mechanisms that alter cognitive processes remain unknown. There is dramatic and selective interneuron death and axonal reorganization within the hippocampus of both humans and animal models, but the functional consequences of these changes on information processing at the neuronal population level have not been well characterized. To examine spatial representations of epileptic and control mice, we developed a novel wire-free miniature microscope to allow for unconstrained behavior during in vivo calcium imaging of neuronal activity. We found that epileptic mice running on a linear track had severely impaired spatial processing in CA1 within a single session, as place cells were less precise and less stable, and population coding was impaired. Long-term stability of place cells was also compromised as place cells in epileptic mice were highly unstable across short time intervals and completely remapped across a week. Because of the large-scale reorganization of inhibitory circuits in epilepsy, we hypothesized that degraded spatial representations were caused by dysfunctional inhibition. To test this hypothesis, we examined the temporal dynamics of hippocampal interneurons using silicon probes to simultaneously record from CA1 and dentate gyrus during head-fixed virtual navigation. We found that epileptic mice had a profound reduction in theta coherence between the dentate gyrus and CA1 regions and altered interneuron synchronization. In particular, dentate interneurons of epileptic mice had altered phase preferences to ongoing theta oscillations, which decorrelated inhibitory population firing between CA1 and dentate gyrus. To assess the specific contribution of desynchronization on spatial coding, we built a CA1 network model to simulate hippocampal desynchronization.Critically, we found that desynchronized inputs reduced the information content and stability of CA1 neurons, consistent with the experimental data. Together, these results demonstrate that temporally precise intra-hippocampal communication is critical for forming the spatial code and that desynchronized firing of hippocampal neuronal populations contributes to poor spatial processing in epileptic mice. 3 Main Text:Temporal lobe epilepsy (TLE) is associated with disabling cognitive deficits 1,2 , interneuron cell death 3,4 , and large-scale anatomical reorganization of limbic circuits [5][6][7][8] in both human patients and rodent models. Following cell death, surviving interneurons from both CA1 and dentate gyrus (DG) sprout new local and long-range connections leading to altered timing and kinetics of inhibition 8-12 . These alterations are likely to have dramatic effects on spatial processing as the hippocampus relies on the precise timing of diverse interneuron subtypes that control excitatory inputs [13][14][15][16] . Indeed, initial studies have shown degraded spatial representations in epileptic rodents 17-20 , but i...

Network Dysfunction in Comorbid Psychiatric Illnesses and Epilepsy

“… 20 , 21 For example, place cells, which are thought to provide a cognitive map, are unstable in epileptic mice, which is associated with interneuron dysfunction and altered oscillations in the hippocampus. 22 , 23 In addition, pathological high-frequency oscillations have been observed during interictal periods and negatively impact memory processes. 24 These data demonstrate that network abnormalities in the hippocampus not only contribute to seizure generation but also lead to impairments in hippocampal function critical for cognitive processes.…”

WONOEP appraisal: Network concept from an imaging perspective

“…The Golshani group is using these microscopes to understand the mechanisms underlying poor spatial memory in temporal lobe epilepsy. By recording place‐related activity in thousands of CA1 neurons over a week, results show dramatic reductions in the number, precision, and stability of place fields …”

“…By recording place-related activity in thousands of CA1 neurons over a week, results show dramatic reductions in the number, precision, and stability of place fields. 35…”

ezTrack: An open-source video analysis pipeline for the investigation of animal behavior

“…A Miniscope was used to image calcium events in the CA1 region of the hippocampus as previously described (Cai et al, 2016;Shuman et al, 2018). The analysis of calcium recordings was performed using an in-house written script based on existing algorithms (Pnevmatikakis et al, 2016;Lu et al, 2018).…”