Resolving the Micro-Macro Disconnect to Address Core Features of Seizure Networks

Abstract

Current drug treatments for epilepsy attempt to broadly restrict excitability to mask a symptom, seizures, with little regard for the heterogeneous mechanisms that underlie disease manifestation across individuals. Here, we discuss the need for a more complete view of epilepsy, outlining how key features at the cellular and microcircuit level can significantly impact disease mechanisms that are not captured by the most common methodology to study epilepsy, electroencephalography (EEG). We highlight how major advances in neuroscience tool development now enable multi-scale investigation of fundamental questions to resolve the currently controversial understanding of seizure networks. These findings will provide essential insight into what has emerged as a disconnect between the different levels of investigation and identify new targets and treatment options.

Pharmaco‐genetic inhibition of pyramidal neurons retards hippocampal kindling‐induced epileptogenesis

“…However, phar- Epileptogenesis is now considered as a circuit-level syndrome pathologically characterized by "excitation-inhibition" imbalance, caused by neuronal loss, synaptic reorganization and circuit rewiring. [38][39][40] Specially, long-term potentiation in glutamatergic transmission plays an important role in epileptogenesis. 41 We , and CaMKIIa-hM4Di mice, respectively.…”

The paradoxical effects of K+channel gain-of-function are mediated by GABAergic neuron hypoexcitability and hyperconnectivity

“…Despite the fact that molecular dysfunction of these channel variants is relatively well-modeled and correctable in heterologous systems, translating these findings to therapies has faced unexpected challenges, likely due to the developmental, cellular, and synaptic complexity of the brain. Progress in tracing the critical steps between ion channel biophysics and pathological synchronization of cortical neurons thus requires precision genetic disease models and multi-level interrogations of their effects (Oyrer et al, 2018, Farrell et al, 2019. To address this, we created a mouse model with a missense mutation in a Na + -activated K + channel gene orthologous to a human missense mutation that causes an early-onset seizure disorder (ADNFLE) and has been shown in heterologous systems to be a GOF variant.…”

Adult-born granule cells support pathological microcircuits in the chronically epileptic dentate gyrus

“…been a longstanding open question in the study of TLE (Farrell et al, 2019). Previous imaging and electrophysiological work examining the role of specific cell types in epileptic pathology has shown that inhibitory circuits play a critical role in shaping interictal dynamics in CA1 (Ewell et al, 2015, Muldoon et al, 2015, Miri et al, 2018.…”

“…Identification and characterization of circuit-level functional organization represents a critical step toward a general framework for resolving the micro-macro disconnect in chronic epilepsies (Farrell et al, 2019). Here we provide the first in vivo characterization of single cell and microcircuit-level dynamics in multiple cell populations in the epileptic DG and relate them to macroscale events in simultaneously recorded LFP.…”

“…Hypersynchronous macrolevel network events associated with TLE, in turn, are thought to be primarily the result of such microlevel alterations to underlying network connectivity within the HPC formation (Netoff et al, 2004, Percha et al, 2005, Dyhrfjeld-Johnsen et al, 2007, Morgan and Soltesz, 2008, Farrell et al, 2019.…”