2003 — 2007 |
Frerking, Matthew E |
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. |
Kainate Receptors On Hippocampal Interneurons @ Oregon Health and Science University
DESCRIPTION (provided by applicant): Inhibitory interneurons in the hippocampus regulate pyramidal cells and prevent hyperexcitability that leads to epileptiform activity. Glutamatergic transmission onto interneurons activates these cells to drive these functions. Recently, it has been shown that hippocampal interneurons express the kainate subtype of ionotropic glutamate receptor, and these kainate receptors (KARs) are synaptically activated. Postsynaptic KARs on interneurons contribute to the excitatory postsynaptic potential (EPSP). KARs on interneurons also depress the release of GABA from interneurons onto pyramidal cells, although the mechanisms underlying this effect remain unclear. These two actions suggest that interneuronal KARs play a major role in the control of inhibitory activity and output in the hippocampus, and possibly represent a therapeutic target to limit hyperexcitability during epilepsy. However, at present it is not possible to critically evaluate this possibility, because insufficient information is available about the functions of interneuronal KARs, the mechanisms by which these functions can be regulated, or the mechanisms by which KARs regulate GABA release. This proposal will seek to address these gaps in our understanding of KARs on interneurons. Using whole-cell patch clamp techniques, the activity of KARs on interneurons will be recorded and manipulated using pharmacological tools. Three specific aims will be addressed. (1) Functions for postsynaptic KARs will be identified, by testing four hypotheses: (a) that KARs are calcium-permeable and can initiate calcium-dependent signaling; (b) that KARs are segregated to different afferent pathways than AMPA receptors; (c) that KARs allow interneurons to perform temporal integration at low afferent firing frequencies; and (d) that these three functions are differentially distributed among different interneuronal subclasses. (2) Mechanisms of regulating the KAR-mediated EPSP will be identified, by testing two hypotheses: (a) that the KAR-mediated EPSP is regulated by continuous receptor delivery to, and removal from, the synapse; and (b) that the KAR-mediated EPSP is subject to activity-dependent synaptic plasticity. (3) Mechanisms underlying the presynaptic actions of interneuronal KARs will be identified, by testing two hypotheses: (a) that glutamate can activate presynaptic KARs that directly regulate GABA release; and (b) that the depression induced by KARs is an indirect consequence of interneuronal spiking. These experiments will provide information about the role of interneuronal KARs in the hippocampus, and provide a rational basis for future experiments to assess the possibility of manipulating these KARs to control hyperexcitability.
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0.958 |
2007 — 2008 |
Frerking, Matthew E |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Synapse Function in a Mouse Model of Alzheimer's Disease @ Oregon Health and Science University
[unreadable] DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive cognitive impairments, most notably memory loss. AD is characterized by neuronal loss and by accumulation of protein deposits (plaques) and neurofibrillary tangles in many brain regions including the hippocampus, a region critical for many forms of learning and memory. The build-up of beta-amyloid peptides, a major component of plaques, is thought to be a causal factor in the cognitive impairments associated with AD, but the physiological effects of beta-amyloid accumulation that would cause these impairments are poorly understood. Our long-term objective is to define physiological mechanisms by which beta-amyloids impair cognition, so that therapies may be developed to protect these mechanisms and thereby limit the damage caused by AD. Recently, several transgenic mouse models for AD have been developed. One of these models, a mouse line with mutations in both amyloid precursor protein (APR) and presenilin-1 (PS-1), has a robust and rapid increase in the levels of beta-amyloids, without formation of tangles or neuronal loss. Hippocampal synaptic function in APP/PS-1 mice is impaired, with early defects in long-term synaptic plasticity and later defects in basal synaptic function. However, the mechanisms underlying these defects remain unknown. In the proposed research, we will identify mechanisms underlying the defects in synaptic function in APP/PS-1 mice. Synaptic properties will be compared in hippocampal slices from APP/PS-1 mice and wild- type littermates, using field potential recordings and whole-cell patch clamp recordings. Two specific aims will be addressed. First, we will identify the synaptic mechanisms that are impaired in these mice during early defects in long-term plasticity, and during late defects in basal synaptic transmission. Second, we will determine whether these defects are caused by the accumulation of beta-amyloids. The proposed research will identify the mechanisms by which APP/PS-1 mutations lead to impaired synaptic function in the hippocampus. Project relevance: The proposed research will identify mechanisms underlying synaptic defects caused by accumulation of beta-amyloids, which is thought to be a major factor in the cognitive impairments in AD. [unreadable] [unreadable] [unreadable]
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0.958 |
2008 — 2012 |
Frerking, Matthew E |
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. |
Hippocampal Synaptic Dynamics During Realistic Patterns of Afferent Activity @ Oregon Health & Science University
DESCRIPTION (provided by applicant): Synaptic transmission is a major mechanism underlying the intercellular transfer and processing of signals in the nervous system. The output of synapses is highly dynamic, owing to the existence of several forms of activity-dependent synaptic plasticity that range in duration from milliseconds to hours. Although individual forms of synaptic plasticity have been well described, the simple stimulus patterns used to define each form of plasticity bear little resemblance to the activity patterns seen in vivo, where most synapses are activated by temporally complex patterns of afferent firing. These complex patterns of activity are expected to engage several forms of synaptic plasticity simultaneously in a complex combination, which we will refer to as synaptic dynamics. Synaptic dynamics determine how the synaptic output produced by each spike is influenced by the pattern of the preceding spike train. These dynamics are widely presumed to be an important component of signal processing during synaptic transmission, and may be affected by drugs or neurological diseases; however, synaptic dynamics during realistic patterns of afferent activity are poorly understood. Our long-term objective is to determine the roles of synaptic dynamics in circuit function in the hippocampus, a brain structure critical in learning and memory. In the present proposal, we will examine synaptic dynamics of Schaffer collateral synapses between CA3 pyramidal cells and CA1 pyramidal cells in hippocampal slices. We will use field and whole-cell recordings to measure synaptic responses to spike trains derived from activity patterns seen in CA3 pyramidal cells in vivo during the performance of a complex behavioral task. We will address three specific aims: 1) to identify functional consequences of synaptic dynamics during behaviorally-relevant patterns of afferent activity; 2) to identify mechanisms that underlie synaptic dynamics; and 3) to determine whether synaptic dynamics can be altered by neuromodulators or long-term plasticity.
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0.958 |
2010 — 2013 |
Frerking, Matthew E |
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. |
Excitatory Synaptic Transmission Onto Hippocampal Interneurons @ Oregon Health & Science University
DESCRIPTION (provided by applicant): The activity and function of cortical circuits depend on the interplay between two interconnected sets of cells: excitatory principal neurons and inhibitory interneurons. Inhibitory interneurons play a critical role in preventing the circuit excitability that leads to epileptiform activity, and also are involved in a number of other processes as well, including regulation and synchronization of firing in principal neurons, release of neuromodulatory peptides, and somatodendritic inhibition of principal neurons. These functions are triggered by interneuronal activation, which occurs through excitatory synaptic transmission onto these cells. This excitatory transmission is primarily glutamatergic, and the excitatory postsynaptic current (EPSC) is mediated largely by ionotropic glutamate receptors of the AMPA receptor (AMPAR) and kainate receptor (KAR) subtypes. We have studied the AMPAR/KAR EPSCs onto hippocampal interneurons located in stratum radiatum and stratum lacunosum-moleculare (SR/SLM). We have found that the EPSC generated by extracellular stimulation has two kinetically distinct components: a rapid, large EPSC that is mediated by AMPARs and is generally similar to AMPAR EPSCs seen throughout the CNS; and a slow, small EPSC that is mediated by both KARs and AMPARs. This slow EPSC lasts for hundreds of milliseconds, which is completely unexpected based on the kinetics of heterologously expressed AMPARs/KARs in response to brief pulses of glutamate. The AMPAR component of the slow EPSC, but not the KAR component, can also be massively potentiated by inhibition of glutamate uptake. These results suggest that the kinetics of the slow EPSC must be determined by a prolonged glutamate transient, or by factors within the interneuron that alter the kinetics of native receptors compared to heterologously expressed receptors, and that the answer may differ depending on the receptor subtype involved and the efficacy of uptake mechanisms. In the proposed research, we will examine the mechanisms underlying the slow EPSC. We will use whole-cell voltage-clamp recording of SR/SLM interneurons in hippocampal slices to record the EPSC, and a variety of pharmacological and genetic manipulations to affect glutamate release, reception, and uptake. Our specific aims are: 1) to test whether the slow AMPAR EPSC is generated by glutamate spillover; 2) to determine whether the receptors underlying the slow EPSC have kinetics that are dictated by receptor subunit composition or interactions with scaffolding proteins; and 3) to define the role of glutamate uptake mechanisms in regulating the slow EPSC.
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0.958 |