Garnik Akopian

University of Southern California, Los Angeles, California, United States

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Publications (25)85.69 Total impact

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    ABSTRACT: Exercise has been shown to be beneficial for Parkinson's disease (PD). A major interest in our lab has been to investigate how exercise modulates basal ganglia function and modifies disease progression. Dopamine (DA) depletion leads to loss of dendritic spines within the caudate nucleus and putamen (striatum) in PD and its animal models and contributes to motor impairments. Striatal medium spiny neurons (MSNs) can be delineated into two populations, the dopamine D1 receptor (DA-D1R)-containing MSNs of the direct pathway and dopamine D2 receptor (DA-D2R)-containing MSNs of the indirect pathway. There is evidence to suggest that the DA-D2R-indirect pathway MSNs may be preferentially affected after DA-depletion with a predominate loss of dendritic spine density when compared to MSNs of the DA-D1R-direct pathway in rodents; however, others have reported that both pathways may be affected in primates. The purpose of this study was to investigate the effects of intensive exercise on dendritic spine density and arborization in MSNs of these two pathways in the MPTP mouse model of PD. We found that MPTP led to a decrease in dendritic spine density in both DA-D1R- and DA-D2R-containing MSNs and 30days of intensive treadmill exercise led to increased dendritic spine density and arborization in MSNs of both pathways. In addition, exercise increased the expression of synaptic proteins PSD-95 and synaptophysin. Taken together these findings support the potential effect of exercise in modifying synaptic connectivity within the DA-depleted striatum and in modifying disease progression in individuals with PD.
    Neurobiology of Disease 12/2013; · 5.62 Impact Factor
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    ABSTRACT: Exercise has been shown to be beneficial for Parkinson's disease (PD). A major interest in our lab has been to investigate how exercise modulates basal ganglia function and modifies disease progression. Dopamine (DA) depletion leads to loss of dendritic spines within the caudate nucleus and putamen (striatum) in PD and its animal models and contributes to motor impairments. Striatal medium spiny neurons (MSNs) can be delineated into two populations, the dopamine D1 receptor (DA-D1R)-containing MSNs of the direct pathway and dopamine D2 receptor (DA-D2R)-containing MSNs of the indirect pathway. There is evidence to suggest that the DA-D2R-indirect pathway MSNs may be preferentially affected after DA-depletion with a predominate loss of dendritic spine density when compared to MSNs of the DA-D1R-direct pathway in rodents; however, others have reported that both pathways may be affected in primates. The purpose of this study was to investigate the effects of intensive exercise on dendritic spine density and arborization in MSNs of these two pathways in the MPTP mouse model of PD. We found that MPTP led to a decrease in dendritic spine density in both DA-D1R- and DA-D2R-containing MSNs and 30days of intensive treadmill exercise led to increased dendritic spine density and arborization in MSNs of both pathways. In addition, exercise increased the expression of synaptic proteins PSD-95 and synaptophysin. Taken together these findings support the potential effect of exercise in modifying synaptic connectivity within the DA-depleted striatum and in modifying disease progression in individuals with PD.
    Neurobiol Dis. 12/2013;
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    ABSTRACT: airborne particulate matter (PM) from urban vehicular aerosols altered glutamate receptor functions and induced glial inflammatory responses in rodent models after chronic exposure. Potential neurotoxic mechanisms were analyzed in vitro. In hippocampal slices, 2 h exposure to aqueous nanosized PM (nPM) selectively altered postsynaptic proteins in CA1 neurons: increased GluA1, GluN2A, and GluN2B, but not GluA2, GluN1 or mGlur5; increased PSD95 and spinophilin, but not synaptophysin, while dentate gyrus (DG) neurons were unresponsive. In hippocampal slices and neurons, MitoSOX red fluorescence was increased by nPM, implying free radical production. Specifically, NO(·) production by slices was increased within 15 min of exposure to nPM with dose dependence, 1-10 μg/ml. Correspondingly, CA1 neurons exhibited increased nitrosylation of the GluN2A receptor and dephosphorylation of GluN2B (S1303) and of GluA1 (S831 & S845). Again, DG neurons were unresponsive to nPM. The induction of NO(·) and nitrosylation were inhibited by AP5, an NMDA receptor antagonist, which also protects neurite outgrowth in vitro from inhibition by nPM. Membrane injury (EthidiumD-1 uptake) showed parallel specificity. Finally, nPM decreased evoked excitatory postsynaptic currents (EPSCs) of CA1 neurons. These findings further document the selective impact of nPM on glutamatergic functions and identify novel responses of NMDA receptor-stimulated NO(·) production and nitrosylation reactions during nPM-mediated neurotoxicity. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 08/2013; · 3.97 Impact Factor
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    ABSTRACT: The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid-type glutamate receptor (AMPAR) plays a critical role in modulating experience-dependent neuroplasticity, and alterations in AMPAR expression may underlie synaptic dysfunction and disease pathophysiology. Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of dopamine (DA) depletion, our previous work showed exercise increases total GluA2 subunit expression and the contribution of GluA2-containing channels in MPTP mice. The purpose of this study was to determine whether exercise-dependent changes in AMPAR expression after MPTP are specific to the striatopallidal (D2 R) or striatonigral (D1 R) medium spiny neuron (MSN) striatal projection pathways. Drd2 -eGFP-BAC transgenic mice were used to delineate differences in AMPAR expression between striatal D2 R-MSNs and D1 R-MSNs. Striatal AMPAR expression was assessed by immunohistochemical (IHC) staining, Western immunoblotting (WB) of preparations enriched for postsynaptic density (PSD), and alterations in the current-voltage relationship of MSNs. We found DA depletion results in the emergence of GluA2-lacking AMPARs selectively in striatopallidal D2 R-MSNs and that exercise reverses this effect in MPTP mice. Exercise-induced changes in AMPAR channels observed after DA depletion were associated with alterations in GluA1 and GluA2 subunit expression in postsynaptic protein, D2 R-MSN cell surface expression, and restoration of corticostriatal plasticity. Mechanisms regulating experience-dependent changes in AMPAR expression may provide innovative therapeutic targets to increase the efficacy of treatments for basal ganglia disorders, including Parkinson's disease. © 2013 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 08/2013; · 2.97 Impact Factor
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    ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer's disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.
    PLoS ONE 01/2013; 8(7):e69830. · 3.73 Impact Factor
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    ABSTRACT: In the central nervous system, two calpain isoforms are highly expressed: calpain1 and calpain2. Here, we show for the first time that activation of the calpain isoform, calpain2, is a necessary event in hippocampal synaptic plasticity and in learning and memory. We developed a fluorescence resonance energy transfer-based animal model to monitor in vivo calpain activation in single cells and in real time. Additionally, utilizing a novel rabies virus glycoprotein-chimeric peptide, which enabled the transvascular delivery of small interfering RNA to the brain against calpain2, we down-regulated the calpain2 isoform in vivo. Calpain2 gene silencing eliminated long-term potentiation and impaired learning and memory. Our results not only identify the calpain2 isoform as a critical mediator in learning and memory but also highlight an innovative, highly efficient calpain2-targeting peptide capable of isoform-specific gene silencing in the brain. We anticipate these innovative technologies and our better understanding of the calpain machinery, particularly of the calpain2 isoform, will have substantial influence on future translational studies, attracting considerable interest in the use of calpain models and calpain-specific inhibitors in the development of therapeutics.
    Neuromolecular medicine 08/2012; · 5.00 Impact Factor
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    ABSTRACT: The striatum is particularly vulnerable to mitochondrial dysfunction and this problem is linked to pathology created by environmental neurotoxins, stimulants like amphetamine, and metabolic disease and ischemia. We studied the course of recovery following a single systemic injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP) and found 3-NP caused lasting changes in motor behavior that were associated with altered activity-dependent plasticity at corticostriatal synapses in Fischer 344 rats. The changes in synapse behavior varied with the time after exposure to the 3-NP injection. The earliest time point studied, 24h after 3-NP, revealed 3-NP-induced an exaggeration of D1 Dopamine (DA) receptor dependent long-term potentiation (LTP) that reversed to normal by 48 h post-3-NP exposure. Thereafter, the likelihood and degree of inducing D2 DA receptor dependent long-term depression (LTD) gradually increased, relative to saline controls, peaking at 1 month after the 3-NP exposure. NMDA receptor binding did not change over the same post 3-NP time points. These data indicate even brief exposure to 3-NP can have lasting behavioral effects mediated by changes in the way DA and glutamate synapses interact.
    Neuroscience 04/2012; 215:149-59. · 3.12 Impact Factor
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    ABSTRACT: The goal of the present investigation was to determine the persistence of striatal (DA) dopaminergic dysfunction after a mild chemically induced hypoxic event in Fisher 344 rats. To this end, we gave a single injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP; 16.5 mg/kg, i.p.) to 2-month old male F344 rats and measured various indices of striatal DA functioning and lipid peroxidation over a 3-month span. Separate groups of rats were used to measure rod walking, evoked DA release, DA content, malondialdehyde (MDA) accumulation, DA receptor binding, and tyrosine hydroxylase (TH) activity. The results showed that 3-NP exposure reduced most measures of DA functioning including motoric ability, DA release, and D(2) receptor densities for 1 to 3 months postdrug administration. Interestingly, DA content was reduced 1 week after 3-NP exposure, but rose to 147% of control values 1 month after 3-NP treatment. MDA accumulation, a measure of lipid peroxidation activity, was increased 24 h and 1 month after 3-NP treatment. 3-NP did not affect TH activity, suggesting that alterations in DA functioning were not the result of nigrostriatal terminal loss. These data demonstrate that a brief mild hypoxic episode caused by 3-NP exposure has long-term detrimental effects on the functioning of the nigrostriatal DA system.
    Synapse 04/2011; 65(4):339-50. · 2.31 Impact Factor
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    ABSTRACT: Epidemiological and clinical studies have suggested that exercise is beneficial for patients with Parkinson's disease (PD). Through research in normal (noninjured) animals, neuroscientists have begun to understand the mechanisms in the brain by which behavioral training and exercise facilitates improvement in motor behavior through modulation of neuronal function and structure, called experience-dependent neuroplasticity. Recent studies are beginning to reveal molecules and downstream signaling pathways that are regulated during exercise and motor learning in animal models of PD and that are important in driving protective and/or adaptive changes in neuronal connections of the basal ganglia and related circuitry. These molecules include the neurotransmitters dopamine and glutamate (and their respective receptors) as well as neurotrophic factors (brain-derived neurotrophic factor). In parallel, human exercise studies have been important in revealing 'proof of concept' including examining the types and parameters of exercise that are important for behavioral/functional improvements and brain changes; the feasibility of incorporating and maintaining an exercise program in individuals with motor disability; and, importantly, the translation and investigation of exercise effects observed in animal studies to exercise effects on brain and behavior in individuals with PD. In this article we highlight findings from both animal and human exercise studies that provide insight into brain changes of the basal ganglia and its related circuitry and that support potentially key parameters of exercise that may lead to long-term benefit and disease modification in PD. In addition, we discuss the current and future impact on patient care and point out gaps in our knowledge where continuing research is needed. Elucidation of exercise parameters important in driving neuroplasticity, as well as the accompanying mechanisms that underlie experience-dependent neuroplasticity may also provide insights towards new therapeutic targets, including neurorestorative and/or neuroprotective agents, for individuals with PD and related neurodegenerative disorders.
    Neurodegenerative disease management. 04/2011; 1(2):157-170.
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    ABSTRACT: Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher pre-pulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors.
    Behavioural brain research 02/2011; 220(2):294-304. · 3.22 Impact Factor
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    ABSTRACT: Since the fi rst identifi cation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a selective neurotoxin for nigrostriatal dopaminergic neurons in 1983, there have been over 2,000 manuscripts published utilizing this compound in mice, attesting to the value of this model. Most of this work is focused on neuroprotection and mechanisms of cell death. While MPTP may not replicate all the features of PD, it provides a key means by which depletion of striatal dopamine can be achieved and by which brain repair mechanism(s) involved in compensation may be studied, including the role of exercise. In this chapter, we have outlined some of the methods utilized in our laboratories to investigate the physiological and molecular correlates of exercise-induced neuroplasticity (brain repair processes) in the MPTP mouse model of PD. Specifi cally, we have shown that both treadmill and voluntary running wheel can be used to modulate motor and nonmotor-related behaviors. We also demonstrate methods used in our
    01/2011: pages 353-369;
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    ABSTRACT: Epidemiological and clinical trials have suggested that exercise is beneficial for patients with Parkinson's disease (PD). However, the underlying mechanisms and potential for disease modification are currently unknown. This review presents current findings from our laboratories in patients with PD and animal models. The data indicate that alterations in both dopaminergic and glutamatergic neurotransmission, induced by activity-dependent (exercise) processes, may mitigate the cortically driven hyper-excitability in the basal ganglia normally observed in the parkinsonian state. These insights have potential to identify novel therapeutic treatments capable of reversing or delaying disease progression in PD.
    Movement Disorders 02/2010; 25 Suppl 1:S141-5. · 4.56 Impact Factor
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    ABSTRACT: Accumulating evidence indicates that the ovarian steroid hormones estrogen and progesterone regulate a wide variety of nonreproductive functions in the central nervous system by interacting with several molecular and cellular processes. A growing literature reporting results obtained in rodent models suggests that 17beta-estradiol, the most potent of the biologically relevant estrogens, facilitates some forms of learning and memory, and in particular, those involving hippocampus-dependent tasks. Hippocampal long-term potentiation and long-term depression of synaptic transmission are types of synaptic plasticity that have been extensively studied, as they are considered as cellular models of memory formation in the brain. In this chapter, we review the literature that analyzes and compares the effects of estrogen and progesterone on synaptic transmission and synaptic plasticity in rodents. Understanding the nonreproductive functions of estrogen and progesterone in the hippocampus has far-reaching implications not only for our basic understanding of neuroendocrinology and neurobiology, but also for developing better treatment of age-related diseases such as Alzheimer's disease.
    Vitamins & Hormones 01/2010; 82:219-39. · 2.30 Impact Factor
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    ABSTRACT: Dopamine depletion leads to impaired motor performance and increased glutamatergic-mediated hyperexcitability of medium spiny neurons in the basal ganglia. Intensive treadmill exercise improves motor performance in both saline treatment and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. In the present study, we investigated the effect of high-intensity treadmill exercise on changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit expression, because these receptor channels confer the majority of fast excitatory neurotransmission in the brain, and their subunit composition provides a key mechanism for regulating synaptic strength and synaptic neuroplasticity and is important in modulating glutamatergic neurotransmission. Within the dorsolateral striatum of MPTP mice, treadmill exercise increased GluR2 subunit expression, with no significant effect on GluR1. Furthermore, neurophysiological studies demonstrated a reduction in the size of excitatory postsynaptic currents (EPSCs) in striatal medium spiny neurons (as determined by the input-output relationship), reduced amplitude of spontaneous EPSCs, and a loss of polyamine-sensitive inward rectification, all supportive of an increase in heteromeric AMPAR channels containing the GluR2 subunit. Phosphorylation of GluR2 at serine 880 in both saline-treated and MPTP mice suggests that exercise may also influence AMPAR trafficking and thus synaptic strength within the striatum. Finally, treadmill exercise also altered flip isoforms of GluR2 and GluR1 mRNA transcripts. These findings suggest a role for AMPARs in mediating the beneficial effects of exercise and support the idea that adaptive changes in GluR2 subunit expression may be important in modulating experience-dependent neuroplasticity of the injured basal ganglia.
    Journal of Neuroscience Research 09/2009; 88(3):650-68. · 2.97 Impact Factor
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    ABSTRACT: The striatum is particularly sensitive to the irreversible inhibitor of succinate dehydrogenase 3-nitropropionic acid (3-NP). In the present study, we examined early changes in behavior and dopamine and glutamate synaptic physiology created by a single systemic injection of 3-NP in Fischer 344 rats. Hindlimb dystonia was seen 2 h after 3-NP injections, and rats performed poorly on balance beam and rotarod motor tests 24 h later. Systemic 3-NP increased NMDA receptor-dependent long-term potentiation (LTP) at corticostriatal synapses over the same time period. The 3-NP-induced corticostriatal LTP was not attributable to increased NMDA receptor number or function, because 3-NP did not change MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine] binding or NMDA/AMPA receptor current ratios. The LTP seen 24 h after 3-NP was D(1) receptor dependent and reversed by exogenous addition of dopamine or a D(2) receptor agonist to brain slices. HPLC and fast-scan cyclic voltammetry revealed a decrease in dopamine content and release in rats injected 24 h earlier with 3-NP, and much like the enhanced LTP, dopamine changes were reversed by 48 h. Tyrosine hydroxylase expression was not changed, and there was no evidence of striatal cell loss at 24-48 h after 3-NP exposure. Sprague Dawley rats showed similar physiological responses to systemic 3-NP, albeit with reduced sensitivity. Thus, 3-NP causes significant changes in motor behavior marked by parallel changes in striatal dopamine release and corticostriatal synaptic plasticity.
    Journal of Neuroscience 10/2008; 28(38):9585-97. · 6.91 Impact Factor
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    ABSTRACT: Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the highest concentration of P4 tested (10(-6) M) decreased the baseline synaptic transmission and magnitude of LTP, but did not affect LTD. Intracellular studies suggest the P4 effect to be mediated, at least in part, by GABA(A) activity. These results establish a general effect of P4 on synaptic transmission, multiple forms of synaptic plasticity, and a possible mechanism of P4 action in hippocampus.
    Learning & memory (Cold Spring Harbor, N.Y.) 02/2008; 15(11):820-2. · 4.08 Impact Factor
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    ABSTRACT: Studies have suggested that there are beneficial effects of exercise in patients with Parkinson's disease, but the underlying molecular mechanisms responsible for these effects are poorly understood. Studies in rodent models provide a means to examine the effects of exercise on dopaminergic neurotransmission. Using intensive treadmill exercise, we determined changes in striatal dopamine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse. C57BL/6J mice were divided into four groups: (1) saline, (2) saline plus exercise, (3) MPTP, and (4) MPTP plus exercise. Exercise was started 5 d after MPTP lesioning and continued for 28 d. Treadmill running improved motor velocity in both exercise groups. All exercised animals also showed increased latency to fall (improved balance) using the accelerating rotarod compared with nonexercised mice. Using HPLC, we found no difference in striatal dopamine tissue levels between MPTP plus exercise compared with MPTP mice. There was an increase detected in saline plus exercise mice. Analyses using fast-scan cyclic voltammetry showed increased stimulus-evoked release and a decrease in decay of dopamine in the dorsal striatum of MPTP plus exercise mice only. Immunohistochemical staining analysis of striatal tyrosine hydroxylase and dopamine transporter proteins showed decreased expression in MPTP plus exercise mice compared with MPTP mice. There were no differences in mRNA transcript expression in midbrain dopaminergic neurons between these two groups. However, there was diminished transcript expression in saline plus exercise compared with saline mice. Our findings suggest that the benefits of treadmill exercise on motor performance may be accompanied by changes in dopaminergic neurotransmission that are different in the injured (MPTP-lesioned) compared with the noninjured (saline) nigrostriatal system.
    Journal of Neuroscience 06/2007; 27(20):5291-300. · 6.91 Impact Factor
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    G Akopian, J P Walsh
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    ABSTRACT: Synaptic plasticity at corticostraital synapses is proposed to fine tune movment and improve motor skills. We found paired-pulse plasticity at corticostriatal synapses reflected variably expressed short-term facilitation blended with a consistent background of longer-lasting depression. Presynaptic modulation via neuotransmitter receptor activation was ruled out as a mechanism for long-lasting paired-pulse depression by examining the effect of selective receptor antagonists. EPSC amplitude and paired-pulse plasticity, however, was influenced by block of D2 dopamine receptors. Block of glutamate transport with l-transdicarboxylic acid (PDC) reduced EPSCs, possibly through a mechanism of AMPA receptor desensitization. Removal of AMPA receptor desensitization with cyclothiazide reduced the paired-pulse depression at long-duration interstimulus intervals (ISIs), indicating that AMPA receptor desensitization participates in corticostriatal paired-pulse plasticity. The low-affinity glutamate receptor antagonist cis-2,3-piperidine dicarboxylic acid (PDA) increased paired-pulse depression, suggesting that a presynaptic component also exists for long-lasting paired-pulse depression. Low Ca(2+)-high Mg(2+) or BAPTA-AM dramatically reduced the amplitude of corticostriatal EPSCs and both manipulations increased the expression of facilitation and, to a lesser extent, they reduced long-lasting paired-pulse depression. EGTA-AM produced a smaller reduction in EPSC amplitude and it did not alter paired-pulse facilitation, but in contrast to low Ca(2+) and BAPTA-AM, EGTA-AM increased long-lasting paired-pulse depression. These experiments suggest that facilitation and depression are sensitive to vesicle depletion, which is dependent upon changes in peak Ca(2+) (i.e. low Ca(2+)-high Mg(2+) or BAPTA-AM). In addition, the action of EGTA-AM suggests that basal Ca(2+) regulates the recovery from long-lasting paired-pulse depression, possibly thourgh a Ca(2+)-sensitive process of vesicle delivery.
    The Journal of Physiology 05/2007; 580(Pt 1):225-40. · 4.38 Impact Factor
  • G Akopian, J P Walsh
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    ABSTRACT: Aging creates deficits in motor performance related to changes in striatal processing of cortical information. This study describes age-related changes in corticostriatal snaptic plasticity and associated mechanisms, which may contribute to declines in motor behavior. Intracellular recordings revealed an age-related decrease in the expression of paired-pulse, posttetanic, and long-term potentiation (LTP). The age-related difference in LTP was associated with reduced sensitivity to block of N-methyl-D-aspartate (NMDA) receptors in the aged population. These age-related changes could not be explained by increased L-type Ca(2+)channel activity, since block of L-type Ca(2+) channels with nifedipine increased rather than decreased the age-related difference in long-term plasticity. Age-related increases in reactive oxygen species (ROS) modulation were also ruled out, since application of H(2)O(2) produced changes in synaptic function that were opposite to trends seen in aging, and addition of the antioxidant Trolox-C had a larger effect on long-term plasticity in young rats than in older rats. A robust age-related difference in long-term synaptic plasticity was found by studying synaptic plasticity following the blocking of D2 receptors with l-sulpiride, which may involve age-difference in NMDA receptor function. l-sulpiride consistently enabled a slow development of LTP at young (but not aged) corticostriatal synapses. However, No age differences were found in the sensitivity to the addition of the D2 receptor agonist quinpirole. These findings provide evidence for age-induced changes in the release properties of cortical terminals and in the functioning of postsynaptic striatal NMDA receptors, which may contribute to age-related deficits in striatum control of movement.
    Synapse 10/2006; 60(3):223-38. · 2.31 Impact Factor
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    ABSTRACT: Glutathione peroxidase (GSHPx) has been demonstrated in several in vivo studies to reduce both the risk and severity of oxidatively-induced tissue damage. The seizure-inducing neurotoxin kainic acid (KA) has been suggested to elicit its toxic effects in part via generation of oxidative stress. In this study, we report that expression of elevated levels of murine GSHPx-1 in transgenic mice surprisingly results in increased rather than decreased KA susceptibility including increased seizure activity and neuronal hippocampal damage. Isolated transgenic primary hippocampal culture neurons also display increased susceptibility to KA treatment compared with those from wildtype animals. This could be due to alterations in the redox state of the glutathione system resulting in elevated glutathione disulfide (GSSG) levels which, in turn, may directly activate NMDA receptors or enhanced response of the NMDA receptor.
    Experimental Neurology 04/2005; 192(1):203-14. · 4.65 Impact Factor

Publication Stats

378 Citations
85.69 Total Impact Points

Institutions

  • 2000–2012
    • University of Southern California
      • Department of Neurology
      Los Angeles, California, United States
  • 2011
    • Gettysburg College
      • Department of Psychology
      Gettysburg, PA, United States
    • California State University, San Bernardino
      • Department of Psychology
      San Bernardino, CA, United States