1991 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurochemical Anatomy of Epilepsy @ University of California Los Angeles
DESCRIPTION: (From Investigator's abstract): The broad goal of this project is to identify and analyze alterations in the neurochemical anatomy of humans and animal models with seizure disorders. Three groups of studies will be included. The first group will focus on the localization of GABA receptors in human and rat control and epileptic tissue since regional differences in the location of the subtypes could have important implications for the basic mechanisms and treatment of seizure disorders. Emphasis will be placed on localization in the hippocampal formation and cerebral cortex. Three methods will be used to provide a comprehensive view of GABA receptor subtype distribution: 1) in situ hybridization to identify neurons that synthesize the different receptor proteins; 2) immunocytochemistry to describe the specific cellular localization of the receptor subtypes; and 3) autoradiography to identify binding patterns of GABA receptor ligands that are similar to those of GABA receptor subtypes. The second group of studies will expand descriptions of morphological reorganization of neurons in the hippocampus of patients with temporal lobe epilepsy (TLE) by ultrastructural analysis of these changes; in situ hybridization studies of prodynorphin mRNA in control and TLE specimens; and descriptions of the circuitry of remaining hippocampal neurons in TLE. The third series of studies will utilize an animal model to determine the types of neurochemical and morphological changes that precede and may underlie increased seizure susceptibility. A rat model of febrile seizures has been selected because febrile convulsions are a common finding in the history of patients with temporal lobe epilepsy. One specific aim is to test the hypothesis that mossy fiber reorganization occurs following hyperthermic seizures during the first two postnatal weeks in the rat.
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1 |
1992 — 1993 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuroanatomical Localization of Gaba-a Receptors @ University of California Los Angeles
DESCRIPTION: (From Investigator's abstract): The broad goal of this project is to identify and analyze alterations in the neurochemical anatomy of humans and animal models with seizure disorders. Three groups of studies will be included. The first group will focus on the localization of GABA receptors in human and rat control and epileptic tissue since regional differences in the location of the subtypes could have important implications for the basic mechanisms and treatment of seizure disorders. Emphasis will be placed on localization in the hippocampal formation and cerebral cortex. Three methods will be used to provide a comprehensive view of GABA receptor subtype distribution: 1) in situ hybridization to identify neurons that synthesize the different receptor proteins; 2) immunocytochemistry to describe the specific cellular localization of the receptor subtypes; and 3) autoradiography to identify binding patterns of GABA receptor ligands that are similar to those of GABA receptor subtypes. The second group of studies will expand descriptions of morphological reorganization of neurons in the hippocampus of patients with temporal lobe epilepsy (TLE) by ultrastructural analysis of these changes; in situ hybridization studies of prodynorphin mRNA in control and TLE specimens; and descriptions of the circuitry of remaining hippocampal neurons in TLE. The third series of studies will utilize an animal model to determine the types of neurochemical and morphological changes that precede and may underlie increased seizure susceptibility. A rat model of febrile seizures has been selected because febrile convulsions are a common finding in the history of patients with temporal lobe epilepsy. One specific aim is to test the hypothesis that mossy fiber reorganization occurs following hyperthermic seizures during the first two postnatal weeks in the rat.
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1 |
1996 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Localization of Two Forms of Glutamate Decarboxylase @ University of California Los Angeles |
1 |
1997 — 1999 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Localization of Two Forms of Glutamate Decarboxy @ University of California Los Angeles
DESCRIPTION (Investigator's Abstract): This is a revised application from an established investigator to characterize the anatomical distribution of two isoforms of glutamate decarboxylase, an essential enzyme for GABA synthesis and to analyze and compare the development of three (-subunits of the GABA-A receptor. The hypothesis is that one of the GAD isoforms -GAD67- plays a "predominant role in the earliest phase of development" The PI will use anatomical methods address four specific aims: (1) to determine if early-appearing hippocampal GAD-containing neurons are analogous to cortical marginal/subplate neurons. The PI will determine the developmental expression of GAD mRNAs; the birthdates of GAD containing neurons; the possibility of cell death among GAD neurons and if early arriving afferents are in close proximity to GAD neurons. (2) The postnatal development of GAD65 and 67 neurons will be described (3) Describe the time course of development and relation to GAD- containing neurons of three (-subunits of the GABA-A receptor. (4) Characterize the ultrastructural localization of the two forms of GAD at two "key" phases of hippocampal development.
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1998 — 2002 |
Houser, Carolyn R |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Plasticity of Gabaa Receptor Subunit Localization @ University of California Los Angeles
The broad goals of this Project are to identify changes in expression of specific subunits of the GABA/A receptor (GABAR) through the use of morphological methods that include in situ hybridization and immunohistochemistry. The studies will focus on two recently observed alterations in GABAR localization and function. First, a marked decrease in expression of the alpha5 subunit has been identified in the pilocarpine model of recurrent seizures, but the factors directly associated with the changes have not been determined. Second, an increase in zinc sensitivity of GBARs has been discovered in the kindling model of epilepsy by Mody, and a major question is whether this might be related to changes in GABAR subunit expression in the vicinity of reorganized mossy fibers. Such findings have led to the following specific aims: 1) Provide ultrastructural descriptions of alpha5 and alpha2 subunit localization in the hippocampal formation where these subunits are abundant; important questions are whether these subunits are located at synaptic or extra- synaptic sites and whether they are present at the same morphologically defined synapses; 2) Determine the subcellular changes that may occur in the alpha5 and alpha2 subunits as immunolabeling is altered in the chronic pilocarpine-treated animals; 3) Test the hypothesis that increased GABAR activation by GABAR agonists or increased levels of intrinsic GABA in the hippocampus will produce decreases in alpha5 subunit expression that are similar to those in chronic pilocarpine-treated rats; 4) Test the hypothesis that GABAR subunit expression is altered in the dentate gyrus of animals with reorganized mossy fibers in ways that could lead to increased zinc sensitivity of GBARs and associated decreases in GABAR function. Subunit changes will be studied in the chronic pilocarpine model and in fully kindled rats. The morphological findings will be related to studies of GABAR function in both models by Mody (Project 3). Alterations in GABAR subunits in the hippocampal formation have relevance for our understanding and treatment of temporal lobe epilepsy and also serve as model systems for studying GABAR subunit function and plasticity in vivo.
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2003 — 2007 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gaba Neurons and Epilepsy @ University of California Los Angeles
[unreadable] DESCRIPTION (provided by applicant): Morphological alterations in GABA neurons in temporal lobe epilepsy are complex and involve the loss of some groups of GABA neurons and the preservation of others. While previous studies have focused primarily on the loss of cell bodies of GABA neurons in epilepsy models, the present studies will examine changes in the distributions of GABAergic axons and terminals. The studies will determine if axonal reorganization of GABA neurons, similar to that of excitatory neurons, occurs in the hippocampal formation in a pilocarpine-treated mouse model of recurrent seizures. The following questions will be addressed: 1) Do remaining somatostatin/GABA neurons in CA1 exhibit axonal reorganization and form an aberrant GABAergic innervation of the molecular layer of the dentate gyrus? Such changes could alter the effectiveness and timing of inhibition in the dentate gyrus. 2) Is a distinct group of GABAergic basket cells that contain cholecystokinin damaged during status epilepticus, and is a loss of these neurons followed by axonal sprouting of a different group of basket cells that express parvalbumin? Such changes could alter the balance between functionally different groups of basket cells and thus alter the inhibitory processes. 3) Is there a maintained reduction of GABAergic fibers in two major dendritic regions of the hippocampus, and is this decreased GABAergic innervation the result of preferential loss of bistratified neurons that innervate the regions? A combination of light and electron microscopic immunohistochemical methods will be used to study the sequential changes of specific groups of GABAergic axons in order to provide solid evidence for initial degeneration of axon terminals and subsequent reorganization or sprouting of GABAergic axons. The results of these studies could help provide an explanation for the paradoxical findings of a substantial loss of some groups of GABA neurons in the hippocampal formation and yet an abundance of GABAergic fibers in the region in temporal lobe epilepsy. The studies could provide new evidence for GABA neuron plasticity in epilepsy that, rather than reducing epileptiform activity, could contribute to the epilepsy process through aberrant inhibitory circuits. [unreadable] [unreadable]
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2005 — 2010 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Gaba Receptor Subunit Plasticity in Epilepsy @ University of California Los Angeles
DESCRIPTION (provided by applicant): Alterations in GABAA receptors (GABARs) are likely to play pivotal roles in temporal lobe epilepsy. It is now recognized that changes in specific GABAR subunits could alter the characteristics of inhibition in seizure-prone brain regions without necessarily producing a massive or generalized loss of inhibition. The delta subunit will be the focus of these studies because GABARs that contain this subunit appear to be uniquely plastic, play an important role in GABA-mediated tonic inhibition and may be major biological targets of neurosteroids in some brain regions such as the dentate gyrus. The broad hypothesis is that changes in delta subunit expression and localization could influence seizure susceptibility by altering tonic inhibition and responsiveness to neurosteroids. Changes will be studied in a pilocarpine-treated mouse model of recurrent seizures and following administration of a synthetic neuroactive steroid. A combination of light and electron microscopic immunohistochemical methods will be used to identify changes in expression and localization of the delta subunit and related GABAR subunits that include alpha4 and gamma2. The following questions will be addressed: 1) Does a decrease in delta subunit expression lead to alterations in the subcellular localization of other GABAR subunits such as gamma2 in a mouse model of epilepsy? 2) What are the morphological and functional characteristics of interneurons that express high levels of the delta subunit in normal and epileptic animals? 3) What GABAR subunits are localized with the delta subunit in neurons of the dentate gyrus? 4) Is delta subunit expression altered by chronic administration of the neuroactive steroid ganaxolone? In all studies, emphasis will be placed on evaluating potential differences between GABAR subunit changes in principal cells and interneurons in the hippocampal formation. The morphological findings will be related to physiological and biochemical studies of GABARs in other components of this program project. The studies could identify new types of GABAR plasticity that could contribute to seizure activity and might also suggest cell-specific targets for pharmacological treatment of epilepsy and related disorders.
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2012 |
Houser, Carolyn R |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
2012 Mechanisms of Epilepsy and Neuronal Synchronization Gordon Research Conferen @ Gordon Research Conferences
DESCRIPTION (provided by applicant): We are requesting NINDS support for a Gordon Research Conference on Mechanisms of Epilepsy and Neuronal Synchronization to be held August 19-24, 2012, at Waterville Valley Resort in New Hampshire. The main goal of the study of seizures is to identify the mechanisms underlying synchronous electrical discharges in neuronal networks in order to develop more effective treatments and cures for epilepsy. A unique, intellectually challenging aspect of epilepsy research arises from the fact that it encompasses virtually all major levels of biological organization, from genes and ion channels to circuits and behavior. The major purpose of this Gordon Research Conference is to bring together geneticists, molecular biologists, developmental neuroscientists, neuroanatomists, electrophysiologists, and computational neuroscientists working on basic mechanisms related either directly or indirectly to seizure generation to synthesize current advances and set the stage for future discoveries. The theme of the current conference is Functional Reorganization in the Epileptic Brain, and the topics to be covered include: 1) Epileptogenesis: Can we prevent it? 2) Seizure generation: Where and how do seizures begin? 3) Circuit Analysis and Dynamics in Epilepsy: Novel approaches; 4) Interneurons: Types, control and dysfunction in epilepsy; 5) Chloride Homeostasis: Are there alterations in epilepsy? 6) Developmental Epilepsies and Co-morbidities: Are there common mechanisms? and 7) Channel Reorganization in the Epileptic Brain: Do genetic alterations suggest treatment targets? Our goals are to disseminate the latest scientific advances, foster productive new insights and collaborations, stimulate an interest in epilepsy research among young investigators; and set the stage for new translational studies that will bring the newest discoveries to the treatment of epilepsy in the shortest possible time. PUBLIC HEALTH RELEVANCE: Epilepsy is a chronic condition that affects 50 million people worldwide. Development of novel therapeutic strategies to better treat and potentially prevent and cure this devastating condition requires scientific advances to increase our understanding of the molecular and cellular mechanisms responsible for epilepsy. This conference will bring together experts from all over the world in an intensive, immersing environment to present and discuss novel findings, facilitate dissemination of knowledge and spawn collaborations. This should significantly advance research directed towards better treatment of epilepsy.
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0.907 |
2012 — 2016 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gaba Receptors and Hilar Neuron Survival in Epilepsy @ University of California Los Angeles
Project Summary Loss of neurons in the hilus of the dentate gyrus is one of the most consistent morphological findings in humans with temporal lobe epilepsy and related models of acquired epilepsy. Two major groups of hilar neurons are frequently damaged, GABAergic somatostatin interneurons and glutamatergic mossy cells. Despite years of interest in hilar neurons, important questions persist. Why are the neurons so vulnerable to excitotoxic damage? How could they be protected? What are the functional effects of both loss and preservation of subgroups of these neurons? A set of new technologies, reagents and mice will now allow probing these questions in exciting new ways. The proposed studies will use mice with Cre-recombinase expression in these neurons to selectively manipulate them through Cre-activated viral gene expression. A combination of light and electron microscopic immunohistochemical methods will be used to evaluate the changes, and functional correlates will be determined with electrophysiological methods. The broad goals are to determine if increasing tonic GABAergic inhibition in these neurons could be neuroprotective and, in a separate set of studies, to map the functional circuits that are activated following manipulation of either mossy cells or somatostatin neurons in normal and seizure-prone animals in vivo. Specific Aim 1 will test the hypothesis that both groups of hilar neurons lack substantial expression of the ¿ subunit of the GABAA receptor (GABAAR) and have low levels of tonic inhibition. Specific Aim 2 will test the hypothesis that expressing an exogenous GABAAR subunit, which is normally involved in tonic inhibition in the cerebellum, will lead to the formation of functional GABAA receptors and increase tonic inhibition in both groups of hilar neurons. Specific Aim 3 will test the hypothesis that increasing tonic inhibition in hilar neurons will protect them from damage following status epilepticus. Specific Aim 4 will examine the functional circuitry of hilar neurons in vivo by using optogenetic methods to manipulate the neurons selectively and then identifying the activated neurons by Fos labeling. The patterns of activation in normal and seizure-prone animals will be compared to test the hypotheses that stimulating remaining mossy cells or silencing remaining somatostatin interneurons in vivo will lead to increased granule cell activation in the epileptic mice. By allowing selective manipulation of hilar neurons in the intact brain, these studies will provide unique views of their function within normal and altered neuronal circuits.
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2012 — 2016 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gaba System Alterations and Fragile X Syndrome @ University of California Los Angeles
DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited cognitive impairment, and children with this disorder often have additional behavioral and neurological problems, including increased anxiety, autistic tendencies, hyperactivity and epilepsy. Since the GABA system plays an important role in regulation of the neural systems involved in these behavioral phenotypes, GABA system deficits could be present in FXS. While alterations in GABAA receptors (GABAARs) have been identified, knowledge of the regional and cellular localization of changes in GABAAR subunits remains very limited. Thus, the broad goal of this project is to test the hypothesis that expression and localization of specific subunits of the GABAAR are altered during postnatal development in a mouse model of FXS and that these changes are associated with functional deficits, including increased neuronal excitability and altered anxiety- related behavior. Specific Aim 1 will identify changes in the 12 subunit of the GABAAR in Fmr1 knockout mice that lack the Fragile X mental retardation protein (FMRP), using immunohistochemical methods. Importantly, the patterns of expression of the 12 subunit will be followed throughout early postnatal development in wild-type and Fmr1 knockout mice in order to identify early changes that could be associated with loss of FMRP function and precede potential compensatory changes that may become apparent later in life. Specific Aim 2 will identify functional deficits that could be associated with altered expression of the 12 subunit in Fmr1 knockout mice. In vitro electrophysiological studies will be used to assess GABAergic function at the axon initial segment of dentate granule cells where the 12 subunit is normally prominent and where a loss of 12 subunit-containing GABAARs could influence axon potential generation and increase granule cell excitability. Behavioral tests will be used to evaluate the anxiolytic and sedative effects of a classical benzodiazepine that could be altered in response to GABAAR subunit changes in Fmr1-deficient mice. Specific Aim 3 will identify changes in the expression and localization of the 4 subunit of the GABAAR in the Fmr1 knockout mouse and determine if such changes are reflected in alterations in tonic inhibition and its modulation by neurosteroids in the dentate gyrus. Specific Aim 4 will determine if GABAAR-related pharmacological treatment will ameliorate some of the behavioral changes and GABAAR subunit deficits in Fmr1 knockout mice. These studies will provide unique information about GABAAR subunit alterations during postnatal development in a mouse model of FXS and could provide a framework for new GABAAR subunit-targeted treatments for this disorder.
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2017 — 2021 |
Golshani, Peyman (co-PI) [⬀] Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epilepsy Related Cell Loss and Cognitive Dysfunction @ University of California Los Angeles
Project Summary Temporal lobe epilepsy is often associated with significant cognitive dysfunction, but the mechanisms underlying such dysfunction are not understood. In both human temporal lobe epilepsy and related models, neuronal loss occurs in selected populations of hippocampal neurons, and this cell loss could be associated with the learning and memory deficits. The effects of loss of each of the most vulnerable groups of neurons are of particular interest, and these neurons include mossy cells in the hilus of the dentate gyrus, hilar somatostatin (SOM) neurons, and SOM neurons in stratum oriens of CA1, the majority of which are oriens lacunosum-moleculare (OLM) neurons. It remains unclear how the loss of each cell type contributes to the reorganization of synaptic connections and alters the in vivo function of hippocampal circuits. The broad goal of this proposal is to determine the effects of selective ablation of each of these three groups of hippocampal neurons and associated axonal reorganization on electrophysiological and behavioral measures of cognitive function. To determine the effects of loss of each cell population, the neurons will be ablated separately through adeno-associated virus (AAV) expression of Cre-dependent diphtheria toxin A in mice with cell-type specific expression of Cre. Specific Aim 1 will test the hypothesis that selective ablation of each of the vulnerable groups of neurons will lead to unique patterns of reorganization of remaining populations of neurons. Cre-dependent transfection of eYFP in Cre-expressing mice will be used to identify changes in the axonal arborizations of remaining neurons and determine if aberrant synaptic circuits are created. Specific Aim 2 will test the hypothesis that mossy cell or hilar SOM neuron deletion, but not OLM neuron deletion, will induce desynchronization of dentate hilar neuron firing during locomotion. Silicon probe recordings of theta oscillations and multiple single-unit recordings of dentate hilar neurons will be used to determine whether mossy cell, hilar SOM interneuron, or SOM OLM deletion induces this desynchronization of dentate hilar neurons. Specific Aim 3 will test the hypothesis that OLM deletion, but not mossy cell or hilar SOM neuron deletion, will cause less precise (broadened) place related firing of CA1 pyramidal neurons. These studies will use calcium imaging of large populations of CA1 neurons in freely moving animals with custom-made miniaturized microscopes to determine which cell type is sufficient for degrading the precision of place field firing. This proposal combines the mutually complementary expertise of two laboratories to determine if loss of specific groups of neurons and related reorganization of hippocampal circuits can lead to changes in how large groups of neurons become synchronized and encode information, and thus contribute to cognitive dysfunction in epilepsy and related disorders.
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2017 — 2020 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gaba Receptor Plasticity and Tonic Inhibition in Epilepsy @ University of California Los Angeles
Project Summary Tonic inhibition is a major form of inhibition in the central nervous system (CNS) and could play a key role in epileptogenesis and seizure generation. Nonsynaptic GABAA receptor (GABAAR) subunits that mediate tonic inhibition, including the ? subunit, are frequently altered in animal models of lesion-induced epilepsy. However, it remains unclear whether several of these changes contribute to or limit seizure activity. It becomes particularly important to understand the functional effects of these changes as new pharmacological agents that can modify the function of ? subunit-containing receptors are developed. A set of new technologies, reagents and mice will be used to study the functional effects of altering GABAAR subunit expression in granule cells of the dentate gyrus which are considered to be major players in seizure generation or propagation within the hippocampal network. The proposed studies will use Cre recombinase-dependent viral vectors to express GABAAR ? subunit selectively in granule cells and determine the effects of this alteration on epileptiform activity within the network in a mouse model of epilepsy. A combination of light and electron microscopic immunohistochemical methods will be used to evaluate changes in GABAAR subunit expression, and the functional correlates will be studied with electrophysiological methods, behavioral memory tasks, and Fos expression as a marker of neuronal activity in vivo. The broad goal of the project is to determine if increasing nonsynaptic GABAAR subunits in a cell-type selective manner will influence tonic inhibition and epileptiform activity in a mouse model of epilepsy. Specific Aim 1 will test the hypothesis that transfection of the ? subunit in dentate granule cells will rescue the decreased expression of this subunit that frequently occurs in mouse models of epilepsy and, in the process, normalize expression of two related subunits, ?4 and ?2, that are also altered in mouse models of epilepsy. Specific Aim 2 will test the hypothesis that an increase in ? subunit expression will enhance GABAAR-mediated tonic inhibition in dentate granule cells and reduce heightened responses of these neurons to perforant path stimulation in seizure-prone mice. Specific Aim 3 will test the hypothesis that increasing ? subunit expression in dentate granule cells will reduce network hyperexcitability and propagation of epileptiform activity in an animal model of epilepsy, using a novel hippocampal-entorhinal cortex slice preparation. Specific Aim 4 will test the hypothesis that enhancing ? subunit expression in dentate granule cells will lead to improved performance on a working memory task in which pilocarpine-treated mice are normally deficient. The effects of increased ? subunit expression on granule cell activity in vivo during an elicited seizure will also be determined. Together these studies will increase our understanding of the effects of altering ? subunit-mediated tonic inhibition selectively in dentate granule cells on hippocampal network function in an animal model of epilepsy. The results could suggest GABAAR subtype and neuron-specific targets for reducing seizure activity and associated cognitive deficits.
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2018 — 2020 |
Houser, Carolyn R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Neuronal Loss in Epileptogenesis @ University of California Los Angeles
Project Summary Cell loss in the hippocampus is one of the most consistent findings in temporal lobe epilepsy (TLE), and two groups of neurons in the dentate gyrus have been identified as potentially the most vulnerable to damage ? somatostatin GABAergic neurons and mossy cells. While these neurons are frequently depleted in epilepsy, numerous other neurons are also lost in the hippocampus and other brain regions, and thus it has remained difficult to establish a strong link between the loss of these particular neurons and the subsequent development of seizures. With the development of new transgenic animals and methods for ablating specific groups of neurons, tools are now available for determining the effects of selective loss of these two groups of neurons in the dentate hilus. The broad hypothesis of this proposal is that selective ablation of both hilar somatostatin neurons and mossy cells will lead to the development of spontaneous seizures. The hypothesis does not imply that this pattern of cell loss is the only or central change that could lead to the development of TLE but, instead, that combined loss of both cell types is sufficient for the development of behavioral seizures and potentially serves as a stimulus for related morphological and functional changes. Specific Aim 1 will test the hypothesis that selective ablation of the two groups of hilar neurons will lead to spontaneous seizures in these animals. Electrographic and behavioral activity will be monitored over time with synchronized video-EEG recordings to identify potential seizure activity and determine the behavioral correlates. Specific Aim 2 will test the hypothesis that selective ablation of these hilar neurons will lead to excessive activity of dentate gyrus granule cells in vivo. Silicon-based probes with microelectrode arrays will be used to characterize granule cell activity and identify early signs of seizure development. Specific Aim 3 will test the hypothesis that selective hilar cell loss will lead to alterations in hippocampal-dependent behavioral tasks. The predicted associated increases in dentate granule cell activity could compromise the ability of the dentate gyrus to limit incoming information, as is necessary for optimal information processing in the hippocampus. Tests of context discrimination and anxiety-like activity will be used to identify the behavioral effects of selective hilar neuron loss. Specific Aim 4 will test the hypothesis that selective hilar cell ablation can serve as a stimulus for axonal reorganization of remaining hippocampal neurons. Neuroanatomical studies will be used to determine if loss of two groups of hilar neurons is sufficient to stimulate sprouting of mossy fibers and remaining GABA neurons, thus replicating changes that are commonly observed in human TLE. The proposed studies could provide the first direct evidence that loss of specific groups of hilar neurons can lead to development of spontaneous seizures, either directly or as a result of related changes in hippocampal circuitry, and could provide a unique model of focal hippocampal (complex partial) seizures.
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