2009 — 2010 |
Mott, David D Reagan, Lawrence P [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Hippocampal Plasticity in Co-Morbid Diabetes and Depression @ University of South Carolina At Columbia
DESCRIPTION (provided by applicant): There is a growing appreciation that the complications of diabetes extend to the central nervous system (CNS), including structural and functional deficits in the hippocampus. Deficits in hippocampal synaptic plasticity are also observed in experimental models of diabetes. One complication that may result from these deficits in hippocampal synaptic plasticity is neurological co-morbidities. In this regard, diabetic patients have higher risk to develop mood disorders like depressive illness when compared to non-diabetic individuals. Unfortunately, the underlying mechanistic links between co-morbid diabetes and depression remain to be identified. One limitation in the use of experimental models of diabetes in the identification of these mechanistic mediators is that diabetic animals exhibit a complex physiology that includes deficits in insulin receptor (IR) signaling, hyperglycemia and neuroendocrine dysfunction. In order to more selectively asses the role of insulin receptor signaling, we recently developed a novel and innovative lentivirus vector that contains an antisense sequence selective for IR (IRAS) that examines the effects of decreasing IR signaling without affecting these other parameters. In this regard, our studies demonstrate that downregulation of hypothalamic IR expression and signaling increases body weight, peripheral adiposity and plasma leptin levels. Downregulation of hypothalamic IRs also elicits deficits in hippocampal synaptic plasticity and impairments in hippocampal-dependent behaviors. As such, downregulation of hypothalamic IRs may provide a novel and innovative approach to examine the mechanistic links between co- morbid diabetes and depression. One potential mechanistic mediator of co-morbid diabetes and depression is leptin. Leptin enhances hippocampal synaptic plasticity and performance of hippocampal-dependent behaviors under normal physiological conditions. Conversely, these parameters are impaired in rodents with genetic deficits in leptin receptor expression. Moreover, leptin resistance in the hypothalamus is proposed to be a hallmark feature of and contributor to diabetes/obesity phenotypes. In view of these observations, we hypothesize that leptin resistance occurs in the hippocampus of rats treated with the IRAS construct that develop an obese/hyperleptinemic phenotype, thereby impairing hippocampal synaptic plasticity and promoting co-morbid depression in diabetic subjects. Hippocampal plasticity in co-morbid diabetes and depression Epidemiological and clinical studies determined that the incidence of major depressive disorder is greater than two fold higher in diabetic patients when compared with non-diabetic patients. These results illustrate that the development and progression of depressive illness is a long-term complication associated with diabetes. Our previous and current data demonstrate that deficits in hippocampal synaptic plasticity are common features of both depressive illness and diabetes. Since leptin is an important mediator of hippocampal synaptic plasticity, while hyperleptinemia is associated with deficits in hippocampal plasticity, the overarching goal of the proposed studies is to determine whether reductions in hypothalamic insulin receptors induces `leptin resistance'in the hippocampus, thereby impairing hippocampal synaptic plasticity. Successful completion of these studies will identify impaired leptin signaling in the hippocampus is an essential mechanistic link between co-morbid diabetes and depression.
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0.923 |
2009 — 2013 |
Fisher, Janet L (co-PI) [⬀] Mott, David D |
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. |
Subunit Dependent Properties of Kainate Receptors @ University of South Carolina At Columbia
DESCRIPTION (provided by applicant): Kainate receptors are glutamate-gated ion channels that mediate synaptic transmission and regulate cellular excitability in the central nervous system. They contribute to cognitive processing by participating in the generation of rhythmic oscillations of hippocampal neurons at behaviorally relevant frequencies. Kainate receptors have also been implicated in a number of neurological disorders including temporal lobe epilepsy, schizophrenia, autism, and neuropathic pain. Rational development of novel therapies targeting these receptors depends upon a better understanding of their function. Kainate receptors are tetrameric and comprised of low affinity GluR5-7 and high affinity KA1 and KA2 subunits. Functional properties of kainite receptors depend upon their subunit composition. In particular, KA2-containing kainate receptors play a distinctive role in neuronal excitation. Current at KA2-containing kainate receptors exhibits a higher conductance and slower decay than that at KA2-lacking kainate receptors. In addition, KA2-containing kainate receptors enhance intrinsic neuronal excitability through a noncanonical metabotropic action. Perhaps because of their importance in neuronal excitation, receptors containing the KA2 subunit exhibit significantly increased sensitivity to modulation by a variety of endogenous agents, including protons, polyamines and zinc. While recent studies have shed light on the roles of KA2-containing kainate receptors in physiological conditions, little is known about how the expression of kainate receptor subunits or the functional role of these receptors changes in disease. Kainate receptors have long been implicated in mechanisms underlying temporal lobe epilepsy. A better understanding of how the properties and regulation of kainate receptors change in temporal lobe epilepsy would provide valuable information in the design of novel therapies for this disease. This project will examine the role of the KA2 subunit in kainate receptors in physiological conditions and in epilepsy. Aim 1 will use recombinant receptors to define the functional contribution of KA2 subunits to kainate receptors. Aim 2 will use lentiviral vectors and pharmacological agents to determine the effect of changes in KA2 subunit expression on KAR-mediated neurotransmission. Aim 3 will use quantitative real time qRT-PCR and immunohistochemistry to determine the time course of changes in KAR subunit RNA and protein in the hippocampus during the development of epilepsy after pilocarpine-induced status epilepticus (SE). Hippocampal slice electrophysiology combined with pharmacological agents and lentiviral vectors will then define how SE-induced alterations in subunit expression change functional properties of kainate receptors at these same time points. PUBLIC HEALTH RELEVANCE: Kainate receptors are glutamate-gated ion channels that are critical for synaptic transmission and can contribute to neurological diseases, such as temporal lobe epilepsy, schizophrenia, autism, and neuropathic pain. The goals of this study are to examine subunit dependent properties of these receptors and the impact of changes in subunit composition on hippocampal function. A better understanding of kainate receptor properties is essential in the rational development of novel therapeutic agents targeted at these receptors.
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0.923 |
2015 — 2019 |
Mcdonald, Alexander Joseph (co-PI) [⬀] Mott, David D |
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. |
Muscarinic Modulation of the Basolateral Amygdala @ University of South Carolina At Columbia
? DESCRIPTION (provided by applicant): Signaling through muscarinic acetylcholine receptors (mAChRs) in the basolateral (BL) nucleus of the amygdala plays an essential role in the formation and extinction of emotional memory. Accordingly, in all mammals, including humans, the BL receives more robust cholinergic innervation than any other target of the basal forebrain. Behavioral studies have demonstrated that activation of mAChRs in BL enhances fear memories, whereas blockade of these receptors prevents memory consolidation. Moreover, Alzheimer's disease as well as neuropsychiatric disorders such as schizophrenia, which are commonly associated with emotional disturbances, are thought to result, at least in part, from abnormal cholinergic transmission. Indeed, in Alzheimer's patients the extent of degeneration of cholinergic input to BL is correlated with their impairment of emotional event memory. These findings clearly suggest that therapeutic modulation of mAChR-mediated mechanisms in the BL could be important for treating a number of major neuropsychiatric diseases involving impairments in emotional learning. Despite the importance of mAChRs in the physiology and pathophysiology of emotional memory, there have been no studies that have systematically examined the molecular, cellular, and network-level mechanisms by which mAChRs regulate BL function. The studies outlined in this proposal will combine multiple-labeling electron microscopy and multiple-labeling confocal immunofluorescence with state-of-the-art electrophysiology and optogenetics to address this significant knowledge gap. Our long term goal is to understand how muscarinic receptor regulation of the amygdala can be manipulated for therapeutic purposes. The objective here is to determine how synaptically released acetylcholine, acting on mAChRs, regulates neuronal activity in the BL. Our central hypothesis is that distinct mAChRs on different neuronal subpopulations play discrete roles in regulating neuronal oscillations, filtering salient signals and strengthening glutamatergic inputs in the BL. Our hypothesis is based on preliminary data which reveal that mAChRs strongly modulate BL circuits in a manner distinct from that reported in other brain regions. This hypothesis will be tested by pursuing three specific aims: 1) To define muscarinic modulation of neuronal excitability and oscillatory activity at pyramidal cells and interneurons in the BL; 2) To define frequency-dependent gating of glutamatergic and GABAergic transmission by presynaptic mAChRs; and 3) To determine the functional effect of mAChRs on synaptic transmission and plasticity in the BL. This project encompasses several of the priorities/themes of the BRAIN Initiative, including characterizing cell types in the nervous system, developing tools to manipulate these precisely defined neurons, creating structural maps of the brain, and crossing boundaries in interdisciplinary collaborations. Information about mAChR regulation of BL circuits will be critical for the development of therapies to ameliorate severe neuropsychiatric disorders, treat drug addiction and diminish the emotional deficits produced by Alzheimer's disease.
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0.923 |