Cell-type specific changes in perisomatic inhibition in an animal model of temporal lobe epilepsy

• Applicants: Professor Dr. Tengis Gloveli; Professor Dr. Imre Vida
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405864679

• Final Report Year: 2025

Final Report Abstract

The hippocampus is a cortical structure with a central position in the distributed declarative memory system of the brain, often affected by brain disorders, including epilepsy. Learning and memory deficits are, therefore, common in both patients and animal models of mesial temporal lobe epilepsy (mTLE). In this proposal, we examined the possibility that properties of two subsets of perisomatic inhibitory interneurons (INs), fast-spiking (FS) and regular-spiking (RS) basket cell (BCs), undergo modification in the epileptic hippocampus affecting network dynamics and function. Specifically, we analysed cell-type specific changes in perisomatic inhibition in the CA3 region of the ventral hippocampus in a mouse model of mTLE. Although in epileptic animals perisomatic INs, as well as pyramidal cells, showed unchanged intrinsic biophysical membrane properties, differences were found in their spatial density and distribution, synaptic properties and contribution to network activity. At the network level, there was a switch in plasticity of sharp-wave-ripples (SWRs) induced by transient gamma oscillations: long-lasting potentiation (network LTP, nLTP) was observed in control network, whereas depression (nLTD) emerged in epilepsy. Metabotropic glutamate receptor 5 (mGluR5) is involved in network plasticity in both control and epileptic animals and its expression was altered in the epileptic hippocampus. Furthermore, we could confirm that nLTD can be observed in hippocampal tissue from drug-resistant epileptic patients. At the level of single INs, cell type-specific difference was found in synaptic plasticity between BC types: FS BCs, providing phasic inhibition, demonstrated long-lasting synaptic potentiation (LTP) in control mice, but showed a loss of LTP in epilepsy. Conversely, RS BCs, mediating tonic inhibition, showed synaptic depression (LTD) in control animals and a loss of LTD in epilepsy. We propose that specific processes involved in the regulation of INs contribute to aberrant network excitability and promote a longlasting depression of network activity in the epileptic hippocampus. A switch from LTP to LTD occurs in the hippocampal circuitry, which can compensate for overexcitation in epilepsy. While cellular morphology and physiology of FS and RS BCs are not changed, they contribute to the altered network plasticity and dynamics.

Publications

• Parvalbumin Interneurons Are Differentially Connected to Principal Cells in Inhibitory Feedback Microcircuits along the Dorsoventral Axis of the Medial Entorhinal Cortex. eneuro, 8(1), ENEURO.0354-20.2020.
  Grosser, Sabine; Barreda, Federico J.; Beed, Prateep; Schmitz, Dietmar; Booker, Sam A. & Vida, Imre
  
• Spatially structured inhibition defined by polarized parvalbumin interneuron axons promotes head direction tuning. Science Advances, 7(25).
  Peng, Yangfan; Barreda Tomas, Federico J.; Pfeiffer, Paul; Drangmeister, Moritz; Schreiber, Susanne; Vida, Imre & Geiger, Jörg R.P.
  
• Cell-Type Specific Inhibition Controls the High-Frequency Oscillations in the Medial Entorhinal Cortex. International Journal of Molecular Sciences, 23(22), 14087.
  Gurgenidze, Shalva; Bäuerle, Peter; Schmitz, Dietmar; Vida, Imre; Gloveli, Tengis & Dugladze, Tamar
  
• Interneuron diversity in the rat dentate gyrus: An unbiased in vitro classification. Hippocampus, 32(4), 310-331.
  Degro, Claudius E.; Bolduan, Felix; Vida, Imre & Booker, Sam A.
  
• Outlines to Initiate Epilepsy Surgery in Low- and Middle-Income Countries. Journal of Integrative Neuroscience, 21(5).
  Bäuerle, Peter; Schneider, Ulf; Holtkamp, Martin; Gloveli, Tengis & Dugladze, Tamar
  
• Cell-type specific inhibitory plasticity in subicular pyramidal cells. Frontiers in Cellular Neuroscience, 18.
  Guinet, Alix; Grosser, Sabine; Özbay, Duru; Behr, Joachim & Vida, Imre
  
• Postsynaptic GABAB‐receptor mediated currents in diverse dentate gyrus interneuron types. Hippocampus, 34(10), 551-562.
  Degro, Claudius E.; Vida, Imre & Booker, Sam A.