Robert J. Morgan

Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures

Many complex neuronal circuits have been shown to display nonrandom features in their connectivity. However, the functional impact of nonrandom network topologies in neurological diseases is not well understood. The dentate gyrus is an excellent circuit in which to study such functional implications because proepileptic insults cause its structure to undergo a number of specific changes in both humans and animals, including the formation of previously nonexistent granule cell-to-granule cell recurrent excitatory connections. Here, we use a large-scale, biophysically realistic model of the epileptic rat dentate gyrus to reconnect the aberrant recurrent granule cell network in four biologically plausible ways to determine how nonrandom connectivity promotes hyperexcitability after injury. We find that network activity of the dentate gyrus is quite robust in the face of many major alterations in granule cell-to-granule cell connectivity. However, the incorporation of a small number of highly interconnected granule cell hubs greatly increases network activity, resulting in a hyperexcitable, potentially seizure-prone circuit. Our findings demonstrate the functional relevance of nonrandom microcircuits in epileptic brain networks, and they provide a mechanism that could explain the role of granule cells with hilar basal dendrites in contributing to hyperexcitability in the pathological dentate gyrus.

Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model

Effective prophylaxis for post-traumatic epilepsy currently does not exist, and clinical trials using anticonvulsant drugs have yielded no long-term antiepileptogenic effects. We report that a single, rapid post-traumatic application of the proconvulsant cannabinoid type-1 (CB1) receptor antagonist SR141716A (Rimonabant-Acomplia) abolishes the long-term increase in seizure susceptibility caused by head injury in rats. These results indicate that, paradoxically, a seizure-enhancing drug may disrupt the epileptogenic process if applied within a short therapeutic time window.

Regulation of Fast-Spiking Basket Cell Synapses by the Chloride Channel ClC–2

Parvalbumin-expressing, fast-spiking basket cells are important for the generation of synchronous, rhythmic population activities in the hippocampus. We found that GABAA receptor–mediated synaptic inputs from murine parvalbumin-expressing basket cells were selectively modulated by the membrane voltage– and intracellular chloride–dependent chloride channel ClC-2. Our data reveal a previously unknown cell type–specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons.

Double Trouble? Potential for Hyperexcitability Following Both Channelopathic up- and Downregulation of Ih in Epilepsy

Studies of pathological ion channel regulation as an underlying mechanism of epilepsy have revealed alterations in the h-current in several animal models. While earlier reports indicate that downregulation of the h-current is pro-excitatory on the single neuron level, we found an upregulation of Ih in hyperexcitable CA1 pyramidal neuron dendrites following experimental febrile seizures. In addition, in several CA1 pyramidal neuron computational models of different complexity, h-current upregulation has been shown to lead to pro-excitable effects. This focused review examines the complex impact of altered h-current on neuronal resting membrane potential (RMP) and input resistance (Rin), as well as reported interactions with other ionic conductances.

Upregulated H-Current in Hyperexcitable CA1 Dendrites after Febrile Seizures

Somatic recordings from CA1 pyramidal cells indicated a persistent upregulation of the h-current (Ih) after experimental febrile seizures. Here, we examined febrile seizure-induced long-term changes in Ih and neuronal excitability in CA1 dendrites. Cell-attached recordings showed that dendritic Ih was significantly upregulated, with a depolarized half-activation potential and increased maximal current. Although enhanced Ih is typically thought to be associated with decreased dendritic excitability, whole-cell dendritic recordings revealed a robust increase in action potential firing after febrile seizures. We turned to computational simulations to understand how the experimentally observed changes in Ih influence dendritic excitability. Unexpectedly, the simulations, performed in three previously published CA1 pyramidal cell models, showed that the experimentally observed increases in Ih resulted in a general enhancement of dendritic excitability, primarily due to the increased Ih-induced depolarization of the resting membrane potential overcoming the excitability-depressing effects of decreased dendritic input resistance. Taken together, these experimental and modeling results reveal that, contrary to the exclusively anti-convulsive role often attributed to increased Ih in epilepsy, the enhanced Ih can co-exist with, and possibly even contribute to, persistent dendritic hyperexcitability following febrile seizures in the developing hippocampus.

Pursuing Paradoxical Proconvulsant Prophylaxis for Epileptogenesis

There are essentially two potential treatment options for any acquired disorder: symptomatic or prophylactic. For acquired epilepsies that follow a variety of different brain insults, there remains a complete lack of prophylactic treatment options, whereas at the same time these epilepsies are notoriously resistant, once they have emerged, to symptomatic treatments with antiepileptic drugs. The development of prophylactic strategies is logistically challenging, both for basic researchers and clinicians. Nevertheless, cannabinoid‐targeting drugs provide a very interesting example of a system within the central nervous system (CNS) that can have very different acute and long‐term effects on hyperexcitability and seizures. In this review, we outline research on cannabinoids suggesting that although cannabinoid antagonists are acutely proconvulsant, they may have beneficial effects on long‐term hyperexcitability following brain insults of multiple etiologies, making them promising candidates for further investigation as prophylactics against acquired epilepsy. We then discuss some of the implications of this finding on future attempts at prophylactic treatments, specifically, the very short window within which prevention may be possible, the possibility that traditional anticonvulsants may interfere with prophylactic strategies, and the importance of moving beyond anticonvulsants—even to proconvulsants—to find the ideal preventative strategy for acquired epilepsy.

Modeling the dentate gyrus.

Computational modeling has become an increasingly useful tool for studying complex neuronal circuits such as the dentate gyrus. In order to effectively apply computational techniques and theories to answer pressing biological questions, however, it is necessary to develop detailed, data-driven models. Development of such models is a complicated process, akin to putting together a jigsaw puzzle with the pieces being such things as cell types, cell numbers, and specific connectivity. This chapter provides a walkthrough for the development of a very large-scale, biophysically realistic model of the dentate gyrus. Subsequently, it demonstrates the utility of a modeling approach in asking and answering questions about both healthy and pathological states involving the modeled brain region. Finally, this chapter discusses some predictions that come directly from the model that can be tested in future experimental approaches.

Computer modeling of epilepsy

This chapter reviews current computational models and proposes future directions for computational modeling in the field of epilepsy. The models include single cells with mutated ion channels; small‐ and large‐scale networks of detailed cells; and macroscopic, mean‐field models of network dynamics. In addition, we consider the potential therapeutic applications of modeling. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado‐Escueta AC, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books).

8 – Functional Consequences of Transformed Network Topology in Hippocampal Sclerosis

Publisher Summary This chapter discusses how computational modeling of the dentate gyrus using large-scale, biophysically realistic, data-driven models allows characterizing the structure of the dentate in both healthy and injured scenarios. It also explores the relationship between the structural alterations that occur after head injury and the function of the dentate gyrus neural network, concluding that structural changes alone can result in hyperexcitability. Computational modeling is a fantastic tool to help isolate and identify the effects of neuronal network architectural alterations. There have been several modeling studies to date that have provided a basis for studying structural changes in disease states, but these studies have used idealized networks that lack many necessary features. In order to model processes involved in epileptogenesis and make confident experimental predictions, model networks must be strongly data-driven and include detailed structural and functional properties. Modelers should also strive to use realistic cell numbers, as scaling can have unpredictable and undesirable effects on such things as efficacy of synaptic inputs and synchronization.

MODELS | Computer Models of Seizures and Epilepsy: Understanding Epileptogenesis using Complex Large-Scale Models

Epilepsy is a network level phenomenon influenced by pathological changes on multiple levels of organization. Over the last several decades, computational modeling has become an increasingly powerful tool for investigating the role of specific pathologies in epileptogenesis. Additionally, recent increases in computational power have made it possible to study structure–function relationships in large brain areas, using complex networks of biologically realistic cells. In this article, we present examples of models that have been especially important for determining the impact of network architectural changes on hyperexcitability following sclerosis of the dentate gyrus. These highly realistic models show that the dentate gyrus is a globally and locally well-connected network with a so-called ‘small world’ structure. Following hilar cell loss and mossy fiber sprouting, this small world network undergoes structural alterations that alone can result in hyperexcitability.