Mind the Gate to Improve Comorbid Cognitive Impairments in Epilepsy.

Abstract

Circuit-Based Interventions in the Dentate Gyrus Rescue Epilepsy-Associated Cognitive Dysfunction Kahn JB, Port GR, Yue C, Takano H, Coulter AD. Brain. 2019;142(9):2705-2721.Temporal lobe epilepsy is associated with significant structural pathology in the hippocampus. In the dentate gyrus, the summative effect of these pathologies is massive hyperexcitability in the granule cells, generating both increased seizure susceptibility and cognitive deficits. To date, therapeutic approaches have failed to improve the cognitive symptoms in fully developed, chronic epilepsy. As the dentate’s principal signaling population, the granule cells’ aggregate excitability has the potential to provide a mechanistically independent downstream target. We examined whether normalizing epilepsy-associated granule cell hyperexcitability—without correcting the underlying structural circuit disruptions—would constitute an effective therapeutic approach for cognitive dysfunction. In the systemic pilocarpine mouse model of temporal lobe epilepsy, the epileptic dentate gyrus excessively recruits granule cells in behavioral contexts, not just during seizure events, and these mice fail to perform on a dentate-mediated spatial discrimination task. Acutely reducing dorsal granule cell hyperactivity in chronically epileptic mice via either of 2 distinct inhibitory chemogenetic receptors rescued behavioral performance such that they responded comparably to wild-type mice. Furthermore, recreating granule cell hyperexcitability in control mice via excitatory chemogenetic receptors, without altering normal circuit anatomy, recapitulated spatial memory deficits observed in epileptic mice. However, making the granule cells overly quiescent in both epileptic and control mice again disrupted behavioral performance. These bidirectional manipulations reveal that there is a permissive excitability window for granule cells that is necessary to support successful behavioral performance. Chemogenetic effects were specific to the targeted dorsal hippocampus, as hippocampal-independent and ventral hippocampal-dependent behaviors remained unaffected. Fos expression demonstrated that chemogenetics can modulate granule cell recruitment via behaviorally relevant inputs. Rather than driving cell activity deterministically or spontaneously, chemogenetic intervention merely modulates the behaviorally permissive activity window in which the circuit operates. We conclude that restoring appropriate principal cell tuning via circuit-based therapies, irrespective of the mechanisms generating the disease-related hyperactivity, is a promising translational approach.