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Lithium increases synaptic GluA2 in hippocampal neurons by elevating the delta-catenin protein

Farooq, Mobeen; Kim, Seonil; Patel, Sunny; Khatri, Latika; Hikima, Takuya; Rice, Margaret E; Ziff, Edward B
Lithium (Li+) is a drug widely employed for treating bipolar disorder, however the mechanism of action is not known. Here we study the effects of Li+ in cultured hippocampal neurons on a synaptic complex consisting of delta-catenin, a protein associated with cadherins whose mutation is linked to autism, and GRIP, an AMPA receptor (AMPAR) scaffolding protein, and the AMPAR subunit, GluA2. We show that Li+ elevates the level of delta-catenin in cultured neurons. delta-catenin binds to the ABP and GRIP proteins, which are synaptic scaffolds for GluA2. We show that Li+ increases the levels of GRIP and GluA2, consistent with Li+-induced elevation of delta-catenin. Using GluA2 mutants, we show that the increase in surface level of GluA2 requires GluA2 interaction with GRIP. The amplitude but not the frequency of mEPSCs was also increased by Li+ in cultured hippocampal neurons, confirming a functional effect and consistent with AMPAR stabilization at synapses. Furthermore, animals fed with Li+ show elevated synaptic levels of delta-catenin, GRIP, and GluA2 in the hippocampus, also consistent with the findings in cultured neurons. This work supports a model in which Li+ stabilizes delta-catenin, thus elevating a complex consisting of delta-catenin, GRIP and AMPARs in synapses of hippocampal neurons. Thus, the work suggests a mechanism by which Li+ can alter brain synaptic function that may be relevant to its pharmacologic action in treatment of neurological disease.
PMID: 27793771
ISSN: 1873-7064
CID: 2288922

mGluR long-term depression regulates GluA2 association with COPII vesicles and exit from the endoplasmic reticulum

Pick, Joseph E; Khatri, Latika; Sathler, Matheus F; Ziff, Edward B
mGluR long-term depression (mGluR-LTD) is a form of synaptic plasticity induced at excitatory synapses by metabotropic glutamate receptors (mGluRs). mGluR-LTD reduces synaptic strength and is relevant to learning and memory, autism, and sensitization to cocaine; however, the mechanism is not known. Here we show that activation of Group I mGluRs in medium spiny neurons induces trafficking of GluA2 from the endoplasmic reticulum (ER) to the synapse by enhancing GluA2 binding to essential COPII vesicle proteins, Sec23 and Sec13. GluA2 exit from the ER further depends on IP3 and Ryanodine receptor-controlled Ca2+ release as well as active translation. Synaptic insertion of GluA2 is coupled to removal of high-conducting Ca2+-permeable AMPA receptors from synapses, resulting in synaptic depression. This work demonstrates a novel mechanism in which mGluR signals release AMPA receptors rapidly from the ER and couple ER release to GluA2 synaptic insertion and GluA1 removal.
PMID: 27856517
ISSN: 1460-2075
CID: 2309982

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

Kim, Seonil; Pick, Joseph E; Abera, Sinedu; Khatri, Latika; Ferreira, Danielle D P; Sathler, Matheus F; Morison, Sage L; Hofmann, Franz; Ziff, Edward B
Phosphorylation of GluA1, a subunit of AMPA receptors (AMPARs), is critical for AMPAR synaptic trafficking and control of synaptic transmission. cGMP-dependent protein kinase II (cGKII) mediates this phosphorylation, and cGKII knockout (KO) affects GluA1 phosphorylation and alters animal behavior. Notably, GluA1 phosphorylation in the KO hippocampus is increased as a functional compensation for gene deletion, while such compensation is absent in the prefrontal cortex. Thus, there are brain region-specific effects of cGKII KO on AMPAR trafficking, which could affect animal behavior. Here, we show that GluA1 phosphorylation levels differ in various brain regions, and specific behaviors are altered according to region-specific changes in GluA1 phosphorylation. Moreover, we identified distinct regulations of phosphatases in different brain regions, leading to regional heterogeneity of GluA1 phosphorylation in the KO brain. Our work demonstrates region-specific changes in GluA1 phosphorylation in cGKII KO mice and corresponding effects on cognitive performance. We also reveal distinct regulation of phosphatases in different brain region in which region-specific effects of kinase gene KO arise and can selectively alter animal behavior.
PMID: 27421896
ISSN: 1549-5485
CID: 2180302

Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant

Kim, Seonil; Violette, Caroline J; Ziff, Edward B
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases characterized by memory loss and cognitive impairment. Whereas most AD cases are sporadic, some are caused by mutations in early-onset familial AD (FAD) genes. One FAD gene encodes presenilin 1 (PS1), and a PS1 mutation in methionine 146 impairs homeostatic synaptic plasticity (HSP). We have previously shown that Ca2+ and calcineurin activity are critical regulators of HSP. Here, we confirm that endoplasmic reticulum-mediated Ca2+ signals are increased in mutant PS1 neurons. We further show that calcineurin activity is abnormally elevated in the mutant and that inhibition of increased calcineurin activity stabilizes GluA1 phosphorylation, promoting synaptic trafficking of Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, contributing to the recovery of impaired HSP found in the mutant. Because HSP is suggested to have roles during learning and memory formation, increased calcineurin activity-induced impairment of HSP can cause cognitive decline in FAD. Thus, reducing abnormally increased calcineurin activity in AD brain may be beneficial for improving AD-related cognitive decline.
PMID: 26455952
ISSN: 1558-1497
CID: 1803572

Persistent pain alters AMPA receptor subunit levels in the nucleus accumbens

Su, Chen; D'amour, James; Lee, Michelle; Lin, Hau-Yeuh; Manders, Toby; Xu, Duo; Eberle, Sarah E; Goffer, Yossef; Zou, Anthony H; Rahman, Maisha; Ziff, Edward; Froemke, Robert C; Huang, Dong; Wang, Jing
BACKGROUND: A variety of pain conditions have been found to be associated with depressed mood in clinical studies. Depression-like behaviors have also been described in animal models of persistent or chronic pain. In rodent chronic neuropathic pain models, elevated levels of GluA1 subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the nucleus accumbens (NAc) have been found to inhibit depressive symptoms. However, the effect of reversible post-surgical pain or inflammatory pain on affective behaviors such as depression has not been well characterized in animal models. Neither is it known what time frame is required to elicit AMPA receptor subunit changes in the NAc in various pain conditions. RESULTS: In this study, we compared behavioral and biochemical changes in three pain models: the paw incision (PI) model for post-incisional pain, the Complete Freund's Adjuvant (CFA) model for persistent but reversible inflammatory pain, and the spared nerve injury (SNI) model for chronic postoperative neuropathic pain. In all three models, rats developed depressive symptoms that were concurrent with the presentation of sensory allodynia. GluA1 levels at the synapses of the NAc, however, differed in these three models. The level of GluA1 subunits of AMPA-type receptors at NAc synapses was not altered in the PI model. GluA1 levels were elevated in the CFA model after a period (7 d) of persistent pain, leading to the formation of GluA2-lacking AMPA receptors. As pain symptoms began to resolve, however, GluA1 levels returned to baseline. Meanwhile, in the SNI model, in which pain persisted beyond 14 days, GluA1 levels began to rise after pain became persistent and remained elevated. In addition, we found that blocking GluA2-lacking AMPA receptors in the NAc further decreased the depressive symptoms only in persistent pain models. CONCLUSION: Our study shows that while both short-term and persistent pain can trigger depression-like behaviors, GluA1 upregulation in the NAc likely represents a unique adaptive response to minimize depressive symptoms in persistent pain states.
PMID: 26260133
ISSN: 1756-6606
CID: 1720982

Limonene reduces hyperalgesia induced by gp120 and cytokines by modulation of NF-kappaB, SOD, IL-1 beta in mice [Meeting Abstract]

Kassuya, C A L; Piccinelli, A C; Morato, P N; Konkiewitz, E C; Ziff, E B; Croda, J
The envelope glycoprotein gp120 of HIV can play an important role in the generation of pain. Intrathecal administration gp120 induces the production of cytokines, including IL-1, IL-6 and TNF, which in turn induces neuroinflammation and hyperalgesia. A previous study from our group demonstrated antihyperalgesic and antidepressive actions of limonene administered orally in a neuropathic pain model. The present work has investigated the antihyperalgesic effects of (R)-(+)-limonene in mice that received intrathecal gp120 by analyzing the roles of cytokines involved in these processes as well as the mechanisms. Male Swiss mice (n = 6) received gp120 (50-500 ng) intrathecally or sterile saline as a control. Intrathecal administration of gp120 increased mechanical sensitivity measured with an electronic Von Frey apparatus, but not cold hypersensitivity (measured by the acetone test), at 2 and 3 h after the injections. Limonene significantly decreased this mechanical sensitivity at 3 h after of the injection. In addition, intrathecal injection of gp120 increased IL-1beta (measured by the ELISA test) in the serum of mice, and limonene prevented the ability of gp120 to increase this cytokine. Limonene also inhibited TNF and IL-1beta-induced mechanical hyperalgesia and IL-1beta-induced cold hypersensitivity. Western blot assay demonstrated limonene was capable of significantly decreasing the expression of NF-kB while limonene increased SOD expression in cytoplasm of cells from spinal cord at 4 h after intrathecal IL-1beta injection. These results demonstrate that gp120 administered intrathecally causes mechanical hyperalgesia and a peripheral increase in IL-1beta, and that limonene inhibits this change. Also limonene modulates the activation of NF-kB and SOD expression in the spinal cord after spinal IL-1beta application. The ability of limonene to inhibit the mechanical hyperalgesia induced by TNF and IL-1beta emphasizes the anti-inflammatory action of limonene, specifically its ability to inhibit cytokine production
ISSN: 1023-3830
CID: 1747722

Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, alpha-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model

Piccinelli, Ana Claudia; Santos, Joyce Alencar; Konkiewitz, Elisabete Castelon; Oesterreich, Silvia Aparecida; Formagio, Anelise Samara Nazari; Croda, Julio; Ziff, Edward Benjamim; Kassuya, Candida Aparecida Leite
Objectives Previous studies have shown that essential oil containing (R)-(+)-limonene and alpha-phellandrene, extracted from fruits of Schinus terebinthifolius Raddi, exhibit anti-inflammatory activity. This work aimed to verify the antihyperalgesic and antidepressive actions of (R)-(+)-limonene, alpha-phellandrene, and essential oil from S. terebinthifolius fruits in spared nerve injury (SNI) model of neuropathic pain in rats. Methods In the present work, essential oil from fruits of S. terebinthifolius, as well as the pure (R)-(+)-limonene and alpha-phellandrene compounds, were assayed for their effects on SNI-induced mechanical and cold hyperalgesia, and depressive-like behavior (immobility in forced swim test) in rats. The locomotor activity was evaluated in open-field test. Results Oral administration for up to 15 days of essential oil of S. terebinthifolius (100 mg/kg), (R)-(+)-limonene (10 mg/kg), alpha-phellandrene (10 mg/kg), and also subcutaneous 10 mg/kg dose of ketamine (positive control) significantly inhibited SNI-induced mechanical hyperalgesia and increased immobility in the forced swim test. On the 15th day of oral treatment, alpha-phellandrene, but neither the essential oil from S. terebinthifolius nor (R)-(+)-limonene, prevented the SNI-induced increase in sensitivity to a cold stimulus. The oral treatment with essential oil (100 mg/kg) or with compounds (10 mg/kg) did not interfere on locomotor activity. Discussion Together, the results of the present work show that essential oil of S. terebinthifolius and compounds present in this oil, including (R)-(+)-limonene and alpha-phellandrene, exhibit antihyperalgesic effects against mechanical hyperalgesia, and are antidepressive, while only alpha-phellandrene inhibited cold hyperalgesia in SNI rats.
PMID: 24661285
ISSN: 1476-8305
CID: 1643952

Episodic sucrose intake during food restriction increases synaptic abundance of AMPA receptors in nucleus accumbens and augments intake of sucrose following restoration of ad libitum feeding

Peng, X-X; Lister, A; Rabinowitsch, A; Kolaric, R; Cabeza de Vaca, S; Ziff, E B; Carr, K D
Weight-loss dieting often leads to loss of control, rebound weight gain, and is a risk factor for binge pathology. Based on findings that food restriction (FR) upregulates sucrose-induced trafficking of glutamatergic AMPA receptors to the nucleus accumbens (NAc) postsynaptic density (PSD), this study was an initial test of the hypothesis that episodic "breakthrough" intake of forbidden food during dieting interacts with upregulated mechanisms of synaptic plasticity to increase reward-driven feeding. Ad libitum (AL) fed and FR subjects consumed a limited amount of 10% sucrose, or had access to water, every other day for 10 occasions. Beginning three weeks after return of FR rats to AL feeding, when 24-h chow intake and rate of body weight gain had normalized, subjects with a history of sucrose intake during FR consumed more sucrose during a four week intermittent access protocol than the two AL groups and the group that had access to water during FR. In an experiment that substituted noncontingent administration of d-amphetamine for sucrose, FR subjects displayed an enhanced locomotor response during active FR but a blunted response, relative to AL subjects, during recovery from FR. This result suggests that the enduring increase in sucrose consumption is unlikely to be explained by residual enhancing effects of FR on dopamine signaling. In a biochemical experiment which paralleled the sucrose behavioral experiment, rats with a history of sucrose intake during FR displayed increased abundance of pSer845-GluA1, GluA2, and GluA3 in the NAc PSD relative to rats with a history of FR without sucrose access and rats that had been AL throughout, whether they had a history of episodic sucrose intake or not. A history of FR, with or without a history of sucrose intake, was associated with increased abundance of GluA1. A terminal 15-min bout of sucrose intake produced a further increase in pSer845-GluA1 and GluA2 in subjects with a history of sucrose intake during FR. Generally, neither a history of sucrose intake nor a terminal bout of sucrose intake affected AMPA receptor abundance in the NAc PSD of AL subjects. Together, these results are consistent with the hypothesis, but the functional contribution of increased synaptic incorporation of AMPA receptors remains to be established.
PMID: 25800309
ISSN: 1873-7544
CID: 1544082

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors

Kim, Seonil; Titcombe, Roseann F; Zhang, Hong; Khatri, Latika; Girma, Hiwot K; Hofmann, Franz; Arancio, Ottavio; Ziff, Edward B
Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca2+ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca2+-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca2+-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.
PMID: 25713349
ISSN: 0027-8424
CID: 1473812

Socioeconomic disadvantage increasing risk for depression among recently diagnosed HIV patients in an urban area in Brazil: cross-sectional study

Nomoto, Silmara Harumi; Longhi, Renata Marrona Praca; de Barros, Bruna Paes; Croda, Julio; Ziff, Edward Benjamin; Castelon Konkiewitz, Elisabete
Depression is the most common psychiatric co-morbidity among people living with HIV (PLHIV), with prevalence rates ranging from 25% to 36%. Depression impacts negatively upon adherence and response to combined antiretroviral therapy (CART) and the transmission of HIV infection through increased sexually risky behavior. This cross-sectional study presents data from a reference HIV-outpatient service in Dourados (Brazil) that evaluated the association between depressive symptoms, health-related quality of life, and clinical, socioeconomic, and demographic factors in newly diagnosed HIV/AIDS patients. Using the Beck Depression Inventory (BDI), the prevalence of depressive symptoms was 61% with a predominance of self-deprecating and cognitive-affective factors. Depressive symptoms were associated with lower income (p = 0.019) and disadvantaged social class (p = 0.005). Poorer quality of life was related to depressive symptoms (p < 0.0001), low educational level (p = 0.05), and lower income (p = 0.03). These data suggest that socioeconomic factors, including level of income and education, are mediating the risk of depression and poor quality of life of PLHIV. Possible explanations for this effect are discussed, including the possible role of stigma.
PMID: 25741909
ISSN: 1360-0451
CID: 1579812