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      Circuit-based interventions in the dentate gyrus rescue epilepsy-associated cognitive dysfunction

      1 , 2 , 3 , 3 , 3 , 4 , 1 , 3 , 5
      Brain
      Oxford University Press (OUP)

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          Abstract

          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 signalling 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 behavioural 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 two distinct inhibitory chemogenetic receptors rescued behavioural 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 behavioural performance. These bidirectional manipulations reveal that there is a permissive excitability window for granule cells that is necessary to support successful behavioural performance. Chemogenetic effects were specific to the targeted dorsal hippocampus, as hippocampal-independent and ventral hippocampal-dependent behaviours remained unaffected. Fos expression demonstrated that chemogenetics can modulate granule cell recruitment via behaviourally relevant inputs. Rather than driving cell activity deterministically or spontaneously, chemogenetic intervention merely modulates the behaviourally 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.

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          Most cited references49

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          Pattern separation in the dentate gyrus and CA3 of the hippocampus.

          Theoretical models have long pointed to the dentate gyrus as a possible source of neuronal pattern separation. In agreement with predictions from these models, we show that minimal changes in the shape of the environment in which rats are exploring can substantially alter correlated activity patterns among place-modulated granule cells in the dentate gyrus. When the environments are made more different, new cell populations are recruited in CA3 but not in the dentate gyrus. These results imply a dual mechanism for pattern separation in which signals from the entorhinal cortex can be decorrelated both by changes in coincidence patterns in the dentate gyrus and by recruitment of nonoverlapping cell assemblies in CA3.
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            Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion.

            Adult-born granule cells (GCs), a minor population of cells in the hippocampal dentate gyrus, are highly active during the first few weeks after functional integration into the neuronal network, distinguishing them from less active, older adult-born GCs and the major population of dentate GCs generated developmentally. To ascertain whether young and old GCs perform distinct memory functions, we created a transgenic mouse in which output of old GCs was specifically inhibited while leaving a substantial portion of young GCs intact. These mice exhibited enhanced or normal pattern separation between similar contexts, which was reduced following ablation of young GCs. Furthermore, these mutant mice exhibited deficits in rapid pattern completion. Therefore, pattern separation requires adult-born young GCs but not old GCs, and older GCs contribute to the rapid recall by pattern completion. Our data suggest that as adult-born GCs age, their function switches from pattern separation to rapid pattern completion. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus.

              The dentate gyrus (DG), in addition to its role in learning and memory, is increasingly implicated in the pathophysiology of anxiety disorders. Here, we show that, dependent on their position along the dorsoventral axis of the hippocampus, DG granule cells (GCs) control specific features of anxiety and contextual learning. Using optogenetic techniques to either elevate or decrease GC activity, we demonstrate that GCs in the dorsal DG control exploratory drive and encoding, not retrieval, of contextual fear memories. In contrast, elevating the activity of GCs in the ventral DG has no effect on contextual learning but powerfully suppresses innate anxiety. These results suggest that strategies aimed at modulating the excitability of the ventral DG may be beneficial for the treatment of anxiety disorders. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Brain
                Oxford University Press (OUP)
                0006-8950
                1460-2156
                September 2019
                September 01 2019
                July 30 2019
                September 2019
                September 01 2019
                July 30 2019
                : 142
                : 9
                : 2705-2721
                Affiliations
                [1 ]Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
                [2 ]Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
                [3 ]The Research Institute of the Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
                [4 ]Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
                [5 ]Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
                Article
                10.1093/brain/awz209
                6736326
                31363737
                7d86515e-66c7-4fef-918e-7cf3a241aa09
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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