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

A major mechanism underlying seizure generation in epileptic networks is an altered balance of excitation and inhibition. In fact, there is strong evidence that dendritic inhibition is reduced in animal models, as well as in human patients with temporal lobe epilepsy (TLE). In contrast, perisomatic inhibition remains unchanged or even increase. However, perisomatic inhibition is provided by two types of GABAergic interneuron which express either parvalbumin (PV) or cholecystokinin (CCK). PV basket cells (BCs) show fast-spiking firing and mediate a rapid, “phasic”-form of inhibition which contributes to the precise timing of discharge and oscillatory synchronization in cortical networks. In contrast, CCK BCs show lower-frequency, regular firing and mediate slower (“tonic”), behavior state-dependent inhibition and modulate neuronal excitability. We propose that the two BC types are differentially affected in epilepsy and contribute to the emergence of seizures and the progression of the disease: inhibition by CCK BCs becomes diminished, therefore neuronal excitability increases and the threshold for seizure generation becomes reduced. In contrast, inhibition by PV BCs is maintained or even increased. However, PV BC-mediated inhibition cannot counterbalance the higher excitability, but rather promotes synchronization and high frequency oscillations, leading to altered rhythmogenesis. Such a mechanism could potentiate seizure generation explaining, at least partially, why drugs enhancing inhibition cannot prevent seizures in some patients.To test these hypotheses, we will apply a combined neuroanatomical, electrophysiological and computational approach focusing on a chronic mouse model of TLE. We will characterize changes in the number, cellular distribution and synaptic connectivity of PV- and CCK BCs in control and epileptic hippocampus using stereological methods. We will investigate changes in the intrinsic and synaptic properties, in particular the regulation of the GABAergic output and postsynaptic excitability by metabotropic receptors, such as GABAB receptors. These physiological investigations will be complemented by quantitative immuno-electron microscopic analysis of ultrastructural and molecular changes. Finally we will analyze how the altered cellular and synaptic properties and the pre- and postsynaptic distribution of GABAB receptors in BCs influence microcircuit interactions and lead to altered rhythmogenesis and the generation of seizures using in vitro slice and computational network models.Results will contribute to our understanding of the divergence of cellular and synaptic mechanisms involved in perisomatic inhibition meditated by PV- and CCK BCs, as well as their differential role in TLE. Furthermore, we will obtain important insights into the mechanisms of altered rhythmogenesis and seizure generation in TLE that can help us better understand drug resistance and identify new therapeutic avenues

• DFG Programme: Research Grants