Multi-modal characterization and simulation of human epileptic circuitry

Abstract

Temporal lobe epilepsy is the fourth most common neurological disorder with about 40% of patients not responding to pharmacological treatment. Increased cellular loss in the hippocampus is linked to disease severity and pathological phenotypes such as heightened seizure propensity.While the hippocampus is the target of therapeutic interventions such as temporal lobe resection, the impact of the disease at the cellular level remains unclear in humans. Here we show that properties of hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from epilepsy patients. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume, surface area and spine density. Single-cell RNA sequencing combined with simulations ascribe the observed electrophysiological changes to gradual modification in three key ion channel conductances: BK, Cav2.2 and Kir2.1. In a bio-realistic computational network model, we show that the changes related to disease progression bring the circuit into a more excitable state. In turn, we observe that by reversing these changes in the three key conductances produces a less excitable, "early disease-like" state. These results provide mechanistic understanding of epilepsy in humans and will inform future therapies such as viral gene delivery to reverse the course of the disorder. Main TextEpilepsy is one of the most common neurologic ailments and temporal lobe epilepsy (TLE) is its most commonly diagnosed form affecting approximately 65 million people worldwide. Despite considerable advances in the diagnosis and treatment of such seizure disorders, the cellular and molecular mechanisms leading to TLE-related seizures remain unclear. Notably, approximately 40% of TLE patients exhibit pharmaco-resistance, i.e. lack of response to conventional

Cell class-specific electric field entrainment of neural activity

“…This, in turn, might affect how human vs. rodent neurons ought to be stimulated to achieve a certain activity pattern. We used our setup to investigate the subthreshold and spiking ES effects of human cortical (temporal or frontal lobe) neurons isolated from neurosurgical specimens 45 .…”

Associations betweenin vitro,in vivoandin silicocell classes in mouse primary visual cortex

“…The experimental data to produce the single-cell models were part of a systematic characterization of mouse visual cortex where a uniform experimental protocol was used to establish a taxonomy based on cellular electrophysiology and morphology 1,24 . Beyond reflecting key properties of various cell types in terms of electrophysiology, morphology and transcriptomics 24,30 , these biophysical single-cell models reproduce EAP signals in the vicinity of the cellular morphology (Fig. 1e, top: spiny cell, cell ID: 395830185; bottom: aspiny cell, cell ID: 469610831).…”

Elucidating memory in the brain via single‐cell transcriptomics

“…Of critical importance to the neuroscience of memory, the hippocampus and the amygdala are brain regions that are conserved in structure and function between mice and humans (Janak & Tye, 2015;Strange et al, 2014). Recent transcriptomics research (Hawrylycz et al, 2012(Hawrylycz et al, , 2015Jaffe et al, 2020), including single-cell RNA sequencing work (Buchin et al, 2020;Zhong et al, 2020), has further illustrated celltype-specific homologies between these species. Thus, transcriptomics offers a high-throughput opportunity to identify cell types within the human hippocampus and amygdala, and moreover allows the possibility to infer functional and behavioral memory mechanisms in the human brain by exploiting homologous rodent cell types (Figure 5).…”

“…(2) they can potentially be obtained from resective surgeries in an intact and living state ex vivo (Buchin et al, 2020). In combination, this allows for in vivo and ex vivo study of the living human brain at a resolution of individual cells.…”

“…Two other prominent advantages of studying the human hippocampus and amygdala are that: (1) they are amenable to being studied in an in vivo setting at a resolution of individual cells (Kaminski et al., 2017; Rutishauser et al., 2011, 2013, 2015); and (2) they can potentially be obtained from resective surgeries in an intact and living state ex vivo (Buchin et al, 2020). In combination, this allows for in vivo and ex vivo study of the living human brain at a resolution of individual cells.…”